4,107 results on '"Cyclin-dependent kinase 6"'
Search Results
2. A Kinome-Wide Synthetic Lethal CRISPR/Cas9 Screen Reveals That mTOR Inhibition Prevents Adaptive Resistance to CDK4/CDK6 Blockade in HNSCC.
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Goto, Yusuke, Koshizuka, Keiichi, Ando, Toshinori, Izumi, Hiroki, Wu, Xingyu, Sato, Kuniaki, Ishikawa, Tomohiko, Ford, Kyle, Feng, Xiaodong, Wang, Zhiyong, Arang, Nadia, Allevato, Michael, Kishore, Ayush, Mali, Prashant, and Gutkind, Jorge
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Humans ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,CRISPR-Cas Systems ,Squamous Cell Carcinoma of Head and Neck ,Piperazines ,Pyridines ,Mice ,Animals ,Drug Resistance ,Neoplasm ,Head and Neck Neoplasms ,Cell Line ,Tumor ,MTOR Inhibitors ,Protein Kinase Inhibitors ,TOR Serine-Threonine Kinases ,Cyclin E ,Xenograft Model Antitumor Assays ,Synthetic Lethal Mutations ,Oncogene Proteins - Abstract
UNLABELLED: The comprehensive genomic analysis of the head and neck squamous cell carcinoma (HNSCC) oncogenome revealed the frequent loss of p16INK4A (CDKN2A) and amplification of cyclin D1 genes in most human papillomavirus-negative HNSCC lesions. However, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown modest effects in the clinic. The aberrant activation of the PI3K/mTOR pathway is highly prevalent in HNSCC, and recent clinical trials have shown promising clinical efficacy of mTOR inhibitors (mTORi) in the neoadjuvant and adjuvant settings but not in patients with advanced HNSCC. By implementing a kinome-wide CRISPR/Cas9 screen, we identified cell-cycle inhibition as a synthetic lethal target for mTORis. A combination of mTORi and palbociclib, a CDK4/6-specific inhibitor, showed strong synergism in HNSCC-derived cells in vitro and in vivo. Remarkably, we found that an adaptive increase in cyclin E1 (CCNE1) expression upon palbociclib treatment underlies the rapid acquired resistance to this CDK4/6 inhibitor. Mechanistically, mTORi inhibits the formation of eIF4G-CCNE1 mRNA complexes, with the consequent reduction in mRNA translation and CCNE1 protein expression. Our findings suggest that mTORi reverts the adaptive resistance to palbociclib. This provides a multimodal therapeutic option for HNSCC by cotargeting mTOR and CDK4/6, which in turn may halt the emergence of palbociclib resistance. SIGNIFICANCE: A kinome-wide CRISPR/Cas9 screen identified cell-cycle inhibition as a synthetic lethal target of mTORis. A combination of mTORi and palbociclib, a CDK4/6-specific inhibitor, showed strong synergistic effects in HNSCC. Mechanistically, mTORis inhibited palbociclib-induced increase in CCNE1.
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- 2024
3. A Study of Abemaciclib (LY2835219) With Abiraterone in Men With Prostate Cancer That Has Spread to Other Parts of the Body and is Expected to Respond to Hormonal Treatment (Metastatic Hormone-Sensitive Prostate Cancer) (CYCLONE 3)
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- 2024
4. Targeting CDK4 and 6 in Cancer Therapy: Emerging Preclinical Insights Related to Abemaciclib
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Wander, Seth A, O’Brien, Neil, Litchfield, Lacey M, O’Dea, Declan, Guimaraes, Claudia Morato, Slamon, Dennis J, and Goel, Shom
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Estrogen ,Breast Cancer ,Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Aminopyridines ,Benzimidazoles ,Breast Neoplasms ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Estrogens ,Female ,Humans ,Mitogens ,Protein Kinase Inhibitors ,Tumor Suppressor Proteins ,abemaciclib ,antitumor ,breast neoplasms ,CDK4 and 6 ,preclinical ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4 and 6) are approved for the treatment of subsets of patients with hormone receptor positive (HR+) breast cancer (BC). In metastatic disease, strategies involving endocrine therapy combined with CDK4 and 6 inhibitors (CDK4 and 6i) improve clinical outcomes in HR+ BCs. CDK4 and 6i prevent retinoblastoma tumor suppressor protein phosphorylation, thereby blocking the transcription of E2F target genes, which in turn inhibits both mitogen and estrogen-mediated cell proliferation. In this review, we summarize preclinical data pertaining to the use of CDK4 and 6i in BC, with a particular focus on several of the unique chemical, pharmacologic, and mechanistic properties of abemaciclib. As research efforts elucidate the novel mechanisms underlying abemaciclib activity, potential new applications are being identified. For example, preclinical studies have demonstrated abemaciclib can exert antitumor activity against multiple tumor types and can cross the blood-brain barrier. Abemaciclib has also demonstrated distinct activity as a monotherapeutic in the treatment of BC. Accordingly, we also discuss how a greater understanding of mechanisms related to CDK4 and 6 blockade highlight abemaciclib's unique in-class properties, and could pave new avenues for enhancing its therapeutic efficacy.
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- 2022
5. Binding selectivity-dependent molecular mechanism of inhibitors towards CDK2 and CDK6 investigated by multiple short molecular dynamics and free energy landscapes
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Lifei Wang, Dan Lu, Yan Wang, Xiaoyan Xu, Peihua Zhong, and Zhiyong Yang
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Cyclin-dependent kinase 2 ,cyclin-dependent kinase 6 ,binding selectivity ,cross-correlation analysis ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Understanding selectivity-dependent molecular mechanism of inhibitors towards CDK2 over CDK6 is prominent for improving drug design towards the CDK family. Multiple short molecular dynamics (MD) simulations combined with MM-GBSA approach are adopted to investigate molecular mechanism on binding selectivity of inhibitors X64, X3A, and 4 AU to CDK2 and CDK6. The RMSF analysis and calculations of molecular surface areas indicate that local structural and global flexibility of CDK6 are stronger than that of CDK2. Based on dynamics cross-correlation maps (DCCMs), motion modes of CDK2 and CDK6 produce difference due to associations of X64, X3A, and 4 AU. The calculated binding free energies (BFEs) demonstrate that the compensation between binding enthalpy and entropy of X64, X34, and 4 AU is a key force driving selectivity of inhibitors towards CDK2 over CDK6. This work provides valuable information for designing highly selective inhibitors towards CDK2 and CDK6 and further promotes identification of efficient anticancer drugs in the future.
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- 2023
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6. Neue Strategien beim metastasierten, endokrin sensitiven Mammakarzinom
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Lüftner, Diana and Wagner, Karola
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- 2024
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7. Binding selectivity-dependent molecular mechanism of inhibitors towards CDK2 and CDK6 investigated by multiple short molecular dynamics and free energy landscapes.
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Wang, Lifei, Lu, Dan, Wang, Yan, Xu, Xiaoyan, Zhong, Peihua, and Yang, Zhiyong
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MOLECULAR dynamics , *CYCLIN-dependent kinases , *DRUG design , *BINDING energy , *INFORMATION design , *ANTINEOPLASTIC agents - Abstract
Understanding selectivity-dependent molecular mechanism of inhibitors towards CDK2 over CDK6 is prominent for improving drug design towards the CDK family. Multiple short molecular dynamics (MD) simulations combined with MM-GBSA approach are adopted to investigate molecular mechanism on binding selectivity of inhibitors X64, X3A, and 4 AU to CDK2 and CDK6. The RMSF analysis and calculations of molecular surface areas indicate that local structural and global flexibility of CDK6 are stronger than that of CDK2. Based on dynamics cross-correlation maps (DCCMs), motion modes of CDK2 and CDK6 produce difference due to associations of X64, X3A, and 4 AU. The calculated binding free energies (BFEs) demonstrate that the compensation between binding enthalpy and entropy of X64, X34, and 4 AU is a key force driving selectivity of inhibitors towards CDK2 over CDK6. This work provides valuable information for designing highly selective inhibitors towards CDK2 and CDK6 and further promotes identification of efficient anticancer drugs in the future. [ABSTRACT FROM AUTHOR]
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- 2023
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8. The prognostic significance of CDK6 expression in renal cell carcinoma treated by immune checkpoint plus tyrosine kinase inhibition.
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Wang, Jiajun, Zhang, Sihong, Wang, Ying, Zhu, Yanjun, Xu, Xianglai, and Guo, Jianming
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RENAL cell carcinoma , *IMMUNE checkpoint proteins , *PROTEIN-tyrosine kinases , *PROTEIN-tyrosine kinase inhibitors , *T cells , *IPILIMUMAB , *GRANZYMES - Abstract
Checkpoint inhibitor immunotherapy plus tyrosine kinase inhibitor (IO/TKI) has become the first‐line treatment for metastatic renal cell carcinoma (RCC), despite the lack of biomarkers. Cyclin‐dependent kinase 6 (CDK6) has shown a regulatory role in antitumour response. The study enrolled two cohorts of metastatic RCC treated by IO/TKI (Zhongshan Hospital [ZS]‐MRCC, n = 45; JAVELIN‐101, n = 726) and two cohorts of localized RCC (ZS‐HRRCC, n = 40; TCGA‐KIRC, n = 530). CDK6 was evaluated by RNA‐sequencing. Progression‐free survival (PFS) was the primary endpoint. The prognostic role of CDK6 was evaluated by survival analysis. The correlation between CDK6 and tumour microenvironment was assessed by immunohistochemistry and flow cytometry. The high‐CDK6 group displayed a lower response rate (13.6%) than the low‐CDK6 group (56.5%) (P =.002). High‐CDK6 was associated with poor PFS in both the ZS‐MRCC cohort (high‐CDK6, median PFS 6.4 months; low‐CDK6, median PFS not reached; P =.010) and JAVELIN‐101 cohort (high‐CDK6, median PFS 10.0 months; low‐CDK6, median PFS 13.3 month; P =.033). High‐CDK6 was associated with increased PD1+CD8+ T cells (Spearman's ρ =.47, P <.001) and decreased Granzyme B+CD8+ T cells (Spearman's ρ = −.35, P =.030). Finally, a random forest score (RFscore) was built by integrating CDK6 and immunologic genes, which was associated with survival benefits of IO/TKI (RFscore‐low, TKI vs IO/TKI, HR = 2.47, 95% CI 1.82–3.35, P <.001; RFscore‐high, TKI vs IO/TKI, HR = 0.99, 95% CI 0.75–1.32, P =.963). Elevated CDK6 expression indicated resistance and poor PFS under IO/TKI therapy, which was related to exhausted CD8+ T cells. Integrated RFscore could evaluate the benefits of IO/TKI. [ABSTRACT FROM AUTHOR]
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- 2023
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9. Inhibition of CDK4/6 promotes CD8 T-cell memory formation
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Heckler, Max, Ali, Lestat R, Clancy-Thompson, Eleanor, Qiang, Li, Ventre, Katherine S, Lenehan, Patrick, Roehle, Kevin, Luoma, Adrienne, Boelaars, Kelly, Peters, Vera, McCreary, Julia, Boschert, Tamara, Wang, Eric S, Suo, Shengbao, Marangoni, Francesco, Mempel, Thorsten R, Long, Henry W, Wucherpfennig, Kai W, Dougan, Michael, Gray, Nathanael S, Yuan, Guo-Cheng, Goel, Shom, Tolaney, Sara M, and Dougan, Stephanie K
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Cancer ,Breast Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Adult ,Aged ,Aminopyridines ,Animals ,Benzimidazoles ,Breast Neoplasms ,Breast Neoplasms ,Male ,CD8-Positive T-Lymphocytes ,Cell Line ,Tumor ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Female ,Humans ,Male ,Mice ,Mice ,Inbred C57BL ,Middle Aged ,Piperazines ,Protein Kinase Inhibitors ,Pyridines ,Oncology and Carcinogenesis - Abstract
CDK4/6 inhibitors are approved to treat breast cancer and are in trials for other malignancies. We examined CDK4/6 inhibition in mouse and human CD8+ T cells during early stages of activation. Mice receiving tumor-specific CD8+ T cells treated with CDK4/6 inhibitors displayed increased T-cell persistence and immunologic memory. CDK4/6 inhibition upregulated MXD4, a negative regulator of MYC, in both mouse and human CD8+ T cells. Silencing of Mxd4 or Myc in mouse CD8+ T cells demonstrated the importance of this axis for memory formation. We used single-cell transcriptional profiling and T-cell receptor clonotype tracking to evaluate recently activated human CD8+ T cells in patients with breast cancer before and during treatment with either palbociclib or abemaciclib. CDK4/6 inhibitor therapy in humans increases the frequency of CD8+ memory precursors and downregulates their expression of MYC target genes, suggesting that CDK4/6 inhibitors in patients with cancer may augment long-term protective immunity. SIGNIFICANCE: CDK4/6 inhibition skews newly activated CD8+ T cells toward a memory phenotype in mice and humans with breast cancer. CDK4/6 inhibitors may have broad utility outside breast cancer, particularly in the neoadjuvant setting to augment CD8+ T-cell priming to tumor antigens prior to dosing with checkpoint blockade.This article is highlighted in the In This Issue feature, p. 2355.
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- 2021
10. Activation of the IFN Signaling Pathway is Associated with Resistance to CDK4/6 Inhibitors and Immune Checkpoint Activation in ER-Positive Breast Cancer
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De Angelis, Carmine, Fu, Xiaoyong, Cataldo, Maria Letizia, Nardone, Agostina, Pereira, Resel, Veeraraghavan, Jamunarani, Nanda, Sarmistha, Qin, Lanfang, Sethunath, Vidyalakshmi, Wang, Tao, Hilsenbeck, Susan G, Benelli, Matteo, Migliaccio, Ilenia, Guarducci, Cristina, Malorni, Luca, Litchfield, Lacey M, Liu, Jiangang, Donaldson, Joshua, Selenica, Pier, Brown, David N, Weigelt, Britta, Reis-Filho, Jorge S, Park, Ben H, Hurvitz, Sara A, Slamon, Dennis J, Rimawi, Mothaffar F, Jansen, Valerie M, Jeselsohn, Rinath, Osborne, C Kent, and Schiff, Rachel
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Genetics ,Breast Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Good Health and Well Being ,Antineoplastic Agents ,Breast Neoplasms ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Female ,Humans ,Piperazines ,Pyridines ,Receptors ,Estrogen ,Signal Transduction ,Tumor Cells ,Cultured ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeCyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) are highly effective against estrogen receptor-positive (ER+)/HER2- breast cancer; however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6i may lead to identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes.Experimental designParental breast cancer cells and their endocrine-resistant derivatives (EndoR) were used. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen deprivation-resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. Gene expression data from CDK4/6i neoadjuvant trials and publicly available datasets were interrogated for correlations of gene signatures and patient outcomes.ResultsParental and EndoR breast cancer lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high IFN signaling and reduced CDK4/6i sensitivity; thus an "IFN-related palbociclib-resistance Signature" (IRPS) was derived. In two neoadjuvant trials of CDK4/6i plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6i. PalboR derivatives displayed dramatic activation of IFN/STAT1 signaling compared with their short-term treated or untreated counterparts. In primary ER+/HER2- tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis.ConclusionsAberrant IFN signaling is associated with intrinsic resistance to CDK4/6i. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN pathway, warranting additional studies to clarify its involvement in resistance to CDK4/6i.
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- 2021
11. Phase I/II Trial of Exemestane, Ribociclib, and Everolimus in Women with HR+/HER2− Advanced Breast Cancer after Progression on CDK4/6 Inhibitors (TRINITI-1)
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Bardia, Aditya, Hurvitz, Sara A, DeMichele, Angela, Clark, Amy S, Zelnak, Amelia, Yardley, Denise A, Karuturi, Meghan, Sanft, Tara, Blau, Sibel, Hart, Lowell, Ma, Cynthia, Rugo, Hope S, Purkayastha, Das, and Moulder, Stacy
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Clinical Research ,Clinical Trials and Supportive Activities ,Patient Safety ,Cancer ,Breast Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adult ,Aged ,Aged ,80 and over ,Aminopyridines ,Androstadienes ,Antineoplastic Combined Chemotherapy Protocols ,Breast Neoplasms ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Disease Progression ,Everolimus ,Female ,Humans ,Middle Aged ,Purines ,Receptor ,ErbB-2 ,Receptor ,erbB-2 ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeStandard-of-care treatment for metastatic hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer includes endocrine therapy (ET) combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Optimal treatment after progression on CDK4/6i is unknown. The TRINITI-1 trial investigated ribociclib, a CDK4/6i that has recently demonstrated significant overall survival benefit in two phase III trials, in combination with everolimus and exemestane in patients with HR+, HER2- advanced breast cancer (ABC) after progression on a CDK4/6i.Patients and methodsThis multicenter, open-label, single-arm, phase I/II study included patients with locally advanced/metastatic HR+/HER2- breast cancer. The primary endpoint was clinical benefit rate (CBR) at week 24 among patients with ET-refractory disease with progression on a CDK4/6i. Other endpoints included safety and biomarker analysis.ResultsOf 104 patients enrolled (phases I and II), 96 had prior CDK4/6i. Recommended phase II doses (all once daily days 1-28 of 28-day cycle) were ribociclib 300 mg, everolimus 2.5 mg, and exemestane 25 mg (group 1) and ribociclib 200 mg, everolimus 5 mg, and exemestane 25 mg (group 2). CBR among 95 efficacy-evaluable patients (phases I and II) at week 24 was 41.1% (95% confidence interval, 31.1-51.6), which met the primary endpoint (predetermined threshold: 10%). Common adverse events included neutropenia (69.2%) and stomatitis (40.4%). No new safety signals were observed; no grade 3/4 QTc prolongation was reported.ConclusionsPreliminary TRINITI-1 safety and efficacy results support further investigation of CDK4/6 blockade and targeting of the PI3K/AKT/mTOR signaling pathway in patients with ET-refractory HR+/HER2- ABC after progression on a CDK4/6i.
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- 2021
12. The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D
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Chaikovsky, Andrea C, Li, Chuan, Jeng, Edwin E, Loebell, Samuel, Lee, Myung Chang, Murray, Christopher W, Cheng, Ran, Demeter, Janos, Swaney, Danielle L, Chen, Si-Han, Newton, Billy W, Johnson, Jeffrey R, Drainas, Alexandros P, Shue, Yan Ting, Seoane, Jose A, Srinivasan, Preethi, He, Andy, Yoshida, Akihiro, Hipkins, Susan Q, McCrea, Edel, Poltorack, Carson D, Krogan, Nevan J, Diehl, J Alan, Kong, Christina, Jackson, Peter K, Curtis, Christina, Petrov, Dmitri A, Bassik, Michael C, Winslow, Monte M, and Sage, Julien
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Genetics ,Cancer ,Underpinning research ,1.1 Normal biological development and functioning ,Adaptor Proteins ,Signal Transducing ,Adenocarcinoma of Lung ,Animals ,Cell Division ,Cyclin D ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Genes ,Tumor Suppressor ,Humans ,Lung Neoplasms ,Mice ,Piperazines ,Pyridines ,U937 Cells ,Ubiquitination ,General Science & Technology - Abstract
The initiation of cell division integrates a large number of intra- and extracellular inputs. D-type cyclins (hereafter, cyclin D) couple these inputs to the initiation of DNA replication1. Increased levels of cyclin D promote cell division by activating cyclin-dependent kinases 4 and 6 (hereafter, CDK4/6), which in turn phosphorylate and inactivate the retinoblastoma tumour suppressor. Accordingly, increased levels and activity of cyclin D-CDK4/6 complexes are strongly linked to unchecked cell proliferation and cancer2,3. However, the mechanisms that regulate levels of cyclin D are incompletely understood4,5. Here we show that autophagy and beclin 1 regulator 1 (AMBRA1) is the main regulator of the degradation of cyclin D. We identified AMBRA1 in a genome-wide screen to investigate the genetic basis of the response to CDK4/6 inhibition. Loss of AMBRA1 results in high levels of cyclin D in cells and in mice, which promotes proliferation and decreases sensitivity to CDK4/6 inhibition. Mechanistically, AMBRA1 mediates ubiquitylation and proteasomal degradation of cyclin D as a substrate receptor for the cullin 4 E3 ligase complex. Loss of AMBRA1 enhances the growth of lung adenocarcinoma in a mouse model, and low levels of AMBRA1 correlate with worse survival in patients with lung adenocarcinoma. Thus, AMBRA1 regulates cellular levels of cyclin D, and contributes to cancer development and the response of cancer cells to CDK4/6 inhibitors.
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- 2021
13. A phase I trial of the CDK 4/6 inhibitor palbociclib in pediatric patients with progressive brain tumors: A Pediatric Brain Tumor Consortium study (PBTC‐042)
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Van Mater, David, Gururangan, Sridharan, Becher, Oren, Campagne, Olivia, Leary, Sarah, Phillips, Joanna J, Huang, Jie, Lin, Tong, Poussaint, Tina Young, Goldman, Stewart, Baxter, Patricia, Dhall, Girish, Robinson, Giles, DeWire‐Schottmiller, Mariko, Hwang, Eugene I, Stewart, Clinton F, Onar‐Thomas, Arzu, Dunkel, Ira J, and Fouladi, Maryam
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Neurosciences ,Pediatric Research Initiative ,Clinical Research ,Rare Diseases ,Pediatric Cancer ,Clinical Trials and Supportive Activities ,Cancer ,Orphan Drug ,Hematology ,Pediatric ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adolescent ,Adult ,Antineoplastic Agents ,Brain Neoplasms ,Child ,Child ,Preschool ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Disease Progression ,Female ,Humans ,Male ,Piperazines ,Protein Kinase Inhibitors ,Pyridines ,Young Adult ,brain tumor ,palbociclib ,PBTC‐ ,042 ,pharmacodynamics ,pharmacokinetics ,PBTC-042 ,Paediatrics and Reproductive Medicine ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Paediatrics - Abstract
BackgroundDisruption of cell-cycle regulators is a potential therapeutic target for brain tumors in children and adolescents. The aim of this study was to determine the maximum tolerated dose (MTD) and describe toxicities related to palbociclib, a selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in pediatric patients with progressive/refractory brain tumors with intact retinoblastoma protein.MethodsPalbociclib was administered orally starting at 50 mg/m2 daily for the first 21 days of a 28-day course. Dose escalation was according to the Rolling-6 statistical design in less heavily (stratum I) and heavily pretreated (stratum II) patients, and MTD was determined separately for each group. Pharmacokinetic studies were performed during the first course, and pharmacodynamic studies were conducted to evaluate relationships between drug levels and toxicities.ResultsA total of 21 patients were enrolled on stratum I and 14 patients on stratum II. The MTD for both strata was 75 mg/m2 . Palbociclib absorption (mean Tmax between 4.9 and 6.6 h) and elimination (mean half-life between 11.3 and 19.5 h) were assessed. The most common toxicity was myelosuppression. Higher palbociclib exposure was associated with grade 3/4 neutropenia and leukopenia. Dose limiting toxicities included grade 4 neutropenia and grade 3 thrombocytopenia and dehydration. No patients had an objective response to palbociclib therapy.ConclusionsPalbociclib was safely administered to children and adolescents at a dosage of 75 mg/m2 for 21 consecutive days followed by seven days of rest in both strata. Future studies will establish its optimal utilization in pediatric patients with brain tumors.
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- 2021
14. Combination of miR-143 and miR-506 reduces lung and pancreatic cancer cell growth through the downregulation of cyclin-dependent kinases
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Hossian, AKM Nawshad, Mackenzie, Gerardo G, and Mattheolabakis, George
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Rare Diseases ,Cancer ,Lung ,Pancreatic Cancer ,Digestive Diseases ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Aminopyridines ,Antineoplastic Agents ,CDC2 Protein Kinase ,Cell Cycle ,Cell Growth Processes ,Cell Line ,Tumor ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Cyclin-Dependent Kinases ,Down-Regulation ,Fibroblasts ,Flavonoids ,Humans ,Lung Neoplasms ,MicroRNAs ,Pancreatic Neoplasms ,Piperidines ,Purines ,Transfection ,Up-Regulation ,miR-143 ,miR-506 ,lung cancer ,pancreatic cancer ,cell cycle ,miR‑143 ,miR‑506 ,Oncology and Carcinogenesis - Abstract
Lung cancer (LC) and pancreatic cancer (PC) are the first and fourth leading causes of cancer‑related deaths in the US. Deregulated cell cycle progression is the cornerstone for rapid cell proliferation, tumor development, and progression. Here, we provide evidence that a novel combinatorial miR treatment inhibits cell cycle progression at two phase transitions, through their activity on the CDK4 and CDK1 genes. Following transfection with miR‑143 and miR‑506, we analyzed the differential gene expression of CDK4 and CDK1, using qPCR or western blot analysis, and evaluated cell cycle inhibition, apoptosis and cytotoxicity. The combinatorial miR‑143/506 treatment downregulated CDK4 and CDK1 levels, and induced apoptosis in LC cells, while sparing normal lung fibroblasts. Moreover, the combinatorial miR treatment demonstrated a comparable activity to clinically tested cell cycle inhibitors in inhibiting cell cycle progression, by presenting substantial inhibition at the G1/S and G2/M cell cycle transitions. More importantly, the miR‑143/506 treatment presented a broader application, effectively downregulating CDK1 and CDK4 levels, and reducing cell growth in PC cells. These findings suggest that the miR‑143/506 combination acts as a promising approach to inhibit cell cycle progression for cancer treatment with minimal toxicity to normal cells.
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- 2021
15. Targeting G1/S phase cell-cycle genomic alterations and accompanying co-alterations with individualized CDK4/6 inhibitor–based regimens
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Kato, Shumei, Okamura, Ryosuke, Adashek, Jacob J, Khalid, Noor, Lee, Suzanna, Nguyen, Van, Sicklick, Jason K, and Kurzrock, Razelle
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Human Genome ,Clinical Trials and Supportive Activities ,Cancer ,Clinical Research ,Genetics ,Breast Cancer ,Development of treatments and therapeutic interventions ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,5.1 Pharmaceuticals ,Good Health and Well Being ,Adult ,Aged ,Aged ,80 and over ,Cyclin D ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Cyclin-Dependent Kinase Inhibitor p15 ,Cyclin-Dependent Kinase Inhibitor p16 ,Female ,G1 Phase Cell Cycle Checkpoints ,Genes ,p16 ,Humans ,MAP Kinase Signaling System ,Male ,Middle Aged ,Neoplasms ,Phosphatidylinositol 3-Kinases ,Progression-Free Survival ,Protein Kinase Inhibitors ,Young Adult ,Cell cycle ,Molecular biology ,Oncology - Abstract
BACKGROUNDAlthough CDK4/6 inhibitors are an established treatment for hormone receptor-positive, HER2-negative metastatic breast cancers, their benefit in other malignancies remains limited.METHODSWe investigated factors associated with clinical outcomes from CDK4/6 inhibitor-based therapy among patients with G1/S phase cell-cycle alterations (CDK4/6 amplifications, CCND1/2/3 amplifications, or CDKN2A/B alterations).RESULTSOverall, 2457 patients with diverse solid tumors that underwent clinical-grade, next-generation sequencing (182-465 genes) and therapy outcome of (non-breast cancer) patients treated with matched CDK4/6 inhibitors were analyzed. G1/S phase cell-cycle alterations occurred in 20.6% (507 of 2457) of patients; 99% of those patients (n = 501) harbored ≥1 characterized co-alteration (median, 4; range, 0-24). In 40 patients with G1/S phase cell-cycle alterations given CDK4/6 inhibitors as part of their regimen, significantly longer median progression-free survival (PFS) was observed when CDK4/6 inhibitor-based therapies matched a larger proportion of tumor alterations, often because CDK4/6 inhibitors were administered together with other drugs that were matched to genomic co-alterations, hence achieving a high matching score (high vs. low [≥50% vs.
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- 2021
16. A Cdk4/6-dependent phosphorylation gradient regulates the early to late G1 phase transition
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Kaulich, Manuel, Link, Verena M, Lapek, John D, Lee, Yeon J, Glass, Christopher K, Gonzalez, David J, and Dowdy, Steven F
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Biochemistry and Cell Biology ,Chemical Sciences ,Biological Sciences ,1.1 Normal biological development and functioning ,Underpinning research ,Generic health relevance ,Cell Cycle Proteins ,Cell Division ,Cells ,Cultured ,Cyclin D ,Cyclin E ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,G1 Phase ,Humans ,Oncogene Proteins ,Phosphorylation ,Proteome ,Proto-Oncogene Proteins ,Retinoblastoma Protein - Abstract
During early G1 phase, Rb is exclusively mono-phosphorylated by cyclin D:Cdk4/6, generating 14 different isoforms with specific binding patterns to E2Fs and other cellular protein targets. While mono-phosphorylated Rb is dispensable for early G1 phase progression, interfering with cyclin D:Cdk4/6 kinase activity prevents G1 phase progression, questioning the role of cyclin D:Cdk4/6 in Rb inactivation. To dissect the molecular functions of cyclin D:Cdk4/6 during cell cycle entry, we generated a single cell reporter for Cdk2 activation, RB inactivation and cell cycle entry by CRISPR/Cas9 tagging endogenous p27 with mCherry. Through single cell tracing of Cdk4i cells, we identified a time-sensitive early G1 phase specific Cdk4/6-dependent phosphorylation gradient that regulates cell cycle entry timing and resides between serum-sensing and cyclin E:Cdk2 activation. To reveal the substrate identity of the Cdk4/6 phosphorylation gradient, we performed whole proteomic and phospho-proteomic mass spectrometry, and identified 147 proteins and 82 phospho-peptides that significantly changed due to Cdk4 inhibition in early G1 phase. In summary, we identified novel (non-Rb) cyclin D:Cdk4/6 substrates that connects early G1 phase functions with cyclin E:Cdk2 activation and Rb inactivation by hyper-phosphorylation.
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- 2021
17. Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer
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O’Brien, Neil A, McDermott, Martina SJ, Conklin, Dylan, Luo, Tong, Ayala, Raul, Salgar, Suruchi, Chau, Kevin, DiTomaso, Emmanuelle, Babbar, Naveen, Su, Faye, Gaither, Alex, Hurvitz, Sara A, Linnartz, Ronald, Rose, Kristine, Hirawat, Samit, and Slamon, Dennis J
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Breast Cancer ,Cancer ,5.1 Pharmaceuticals ,6.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Evaluation of treatments and therapeutic interventions ,Good Health and Well Being ,Animals ,Breast Neoplasms ,Cell Line ,Tumor ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Drug Evaluation ,Preclinical ,Drug Resistance ,Neoplasm ,Estrogen Receptor alpha ,Female ,Humans ,Mice ,Nude ,Molecular Targeted Therapy ,Phosphatidylinositol 3-Kinases ,Pregnancy ,Protein Kinase Inhibitors ,Signal Transduction ,TOR Serine-Threonine Kinases ,Xenograft Model Antitumor Assays ,Palbociclib ,Alpelisib ,Translational ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
BackgroundCombined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/HER2- breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance.MethodsIn this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance.ResultsWe show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2- breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2- breast cancer models.ConclusionsThese data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2- breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.
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- 2020
18. Combination of cyclin-dependent kinase and immune checkpoint inhibitors for the treatment of bladder cancer
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Long, Qilai, Ma, Ai-Hong, Zhang, Hongyong, Cao, Zhixiu, Xia, Roger, Lin, Tzu-Yin, Sonpavde, Guru P, de Vere White, Ralph, Guo, Jianming, and Pan, Chong-Xian
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Urologic Diseases ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Good Health and Well Being ,Animals ,Antineoplastic Agents ,Immunological ,Antineoplastic Combined Chemotherapy Protocols ,Apoptosis ,Cell Proliferation ,Cell Survival ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Deoxycytidine ,Humans ,Mice ,Piperazines ,Programmed Cell Death 1 Receptor ,Protein Kinase Inhibitors ,Pyridines ,Urinary Bladder Neoplasms ,Xenograft Model Antitumor Assays ,Gemcitabine ,CDK4 ,6 ,Targeted therapy ,Chemotherapy ,Immunotherapy ,Bladder cancer ,Patient-derived xenograft ,CDK4/6 ,Oncology and carcinogenesis - Abstract
BackgroundPerturbation of the CDK4/6 pathway is frequently observed in advanced bladder cancer. We investigated the potential of targeting this pathway alone or in combination with chemotherapy or immunotherapy as a therapeutic approach for the treatment of bladder cancer METHODS: The genetic alterations of the CDK4/6 pathway in bladder cancer were first analyzed with The Cancer Genome Atlas database and validated in our bladder cancer patient-derived tumor xenografts (PDXs). Bladder cancer cell lines and mice carrying PDXs with the CDK4/6 pathway perturbations were treated with a CDK4/6 inhibitor palbociclib to determine its anticancer activity and the underlying mechanisms. The combination index method was performed to assess palbociclib and gemcitabine drug-drug interactions. Syngeneic mouse bladder cancer model BBN963 was used to assess whether palbociclib could potentiate anti-PD1 immunotherapy.ResultsOf the 413 bladder cancer specimens, 79.2% harbored pertubations along the CDK4/6 pathway. Palbociclib induced G0/G1 cell cycle arrest but with minimal apoptosis in vitro. In mice carrying PDXs, palbociclib treatment reduced tumor growth and prolonged survival from 14 to 32 days compared to vehicle only controls (p = 0.0001). Palbociclib treatment was associated with a decrease in Rb phosphorylation in both cell lines and PDXs. Palbociclib and gemcitabine exhibited antagonistic cytotoxicity in vitro (CI > 3) and in vivo, but palbociclib significantly enhanced the treatment efficacy of anti-PD1 immunotherapy and induced CD8+ T lymphocyte infiltration in syngeneic mouse models.ConclusionsThe CDK4/6 pathway is feasible as a potential target for the treatment of bladder cancer, especially in combination with immunotherapy. A CDK4/6 inhibitor should not be combined with gemcitabine.
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- 2020
19. Identification of abemaciclib derivatives targeting cyclin-dependent kinase 4 and 6 using molecular dynamics, binding free energy calculation, synthesis, and pharmacological evaluation.
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Yanting Zhou, Xiandeng Li, Peifang Luo, Huiting Chen, Yan Zhou, Xueting Zheng, Yuan Yin, Haoche Wei, Hongji Liu, Wen Xia, Mingsong Shi, and Xiaoan Li
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MOLECULAR dynamics ,CYCLIN-dependent kinases ,CYCLIN-dependent kinase inhibitors ,DRUG efficacy ,HYDROGEN bonding ,MOLECULAR docking - Abstract
CDK4/6 plays a crucial role in various cancers and is an effective anticancer drug target. However, the gap between clinical requirements and approved CDK4/6 drugs is unresolved. Thus, there is an urgent need to develop selective and oral CDK4/6 inhibitors, particularly for monotherapy. Here, we studied the interaction between abemaciclib and human CDK6 using molecular dynamics simulations, binding free energy calculations, and energy decomposition. V101 and H100 formed stable hydrogen bonds with the amine-pyrimidine group, and K43 interacted with the imidazole ring via an unstable hydrogen bond. Meanwhile, I19, V27, A41, and L152 interacted with abemaciclib through p-alkyl interactions. Based on the binding model, abemaciclib was divided into four regions. With one region modification, 43 compounds were designed and evaluated using molecular docking. From each region, three favorable groups were selected and combined with each other to obtain 81 compounds. Among them, C2231-A, which was obtained by removing the methylene group from C2231, showed better inhibition than C2231. Kinase profiling revealed that C2231-A showed inhibitory activity similar to that of abemaciclib; additionally, C2231-A inhibited the growth of MDA-MB-231 cells to a greater extent than did abemaciclib. Based on molecular dynamics simulation, C2231-A was identified as a promising candidate compound with considerable inhibitory effects on human breast cancer cell lines. [ABSTRACT FROM AUTHOR]
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- 2023
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20. Early treatment-related neutropenia predicts response to palbociclib
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McAndrew, Nicholas P, Dickson, Mark A, Clark, Amy S, Troxel, Andrea B, O’Hara, Mark H, Colameco, Christopher, Gallager, Maryann, Gramlich, Kristi, Zafman, Kelly, Vaughn, David, Schwartz, Gary K, O’Dwyer, Peter J, and DeMichele, Angela
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Clinical Research ,Breast Cancer ,Clinical Trials and Supportive Activities ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Female ,Humans ,Male ,Middle Aged ,Neoplasms ,Neutropenia ,Piperazines ,Proportional Hazards Models ,Protein Kinase Inhibitors ,Pyridines ,Young Adult ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundPalbociclib is highly active in oestrogen-receptor positive (ER+) metastatic breast cancer, but neutropenia is dose limiting. The goal of this study was to determine whether early neutropenia is associated with disease response to single-agent palbociclib.MethodsBlood count and disease-response data were analysed from two Phase 2 clinical trials at different institutions using single-agent palbociclib: advanced solid tumours positive for retinoblastoma protein and advanced liposarcoma. The primary endpoint was PFS. The primary exposure variable was the nadir absolute neutrophil count (ANC) during the first two cycles of treatment.ResultsOne hundred and ninety-six patients (61 breast, 135 non-breast) were evaluated between the two trials. Development of any grade neutropenia was significantly associated with longer median PFS in both the breast cancer (HR 0.29, 95% CI 0.11-0.74, p = 0.010) and non-breast cancer (HR 0.57, 95% CI 0.38-0.85, p = 0.006) cohorts. Grade 3-4 neutropenia was significantly associated with prolonged PFS in the non-breast cohort (HR 0.57, 95% CI 0.38-0.85, p = 0.006) but not in the breast cohort (HR 0.87, 95% CI 0.51-1.47, p = 0.596). Multivariate analysis yielded similar results.ConclusionsTreatment-related neutropenia in the first two cycles was significantly and independently associated with prolonged PFS, suggesting that neutropenia may be a useful pharmacodynamic marker to guide individualised palbociclib dosing.Clinical trials registration informationBasket Trial: NCT01037790; Sarcoma Trial: NCT01209598.
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- 2020
21. Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer.
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O'Brien, Neil A, McDermott, Martina SJ, Conklin, Dylan, Luo, Tong, Ayala, Raul, Salgar, Suruchi, Chau, Kevin, DiTomaso, Emmanuelle, Babbar, Naveen, Su, Faye, Gaither, Alex, Hurvitz, Sara A, Linnartz, Ronald, Rose, Kristine, Hirawat, Samit, and Slamon, Dennis J
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Cell Line ,Tumor ,Animals ,Humans ,Mice ,Nude ,Breast Neoplasms ,Estrogen Receptor alpha ,Protein Kinase Inhibitors ,Drug Evaluation ,Preclinical ,Xenograft Model Antitumor Assays ,Signal Transduction ,Pregnancy ,Drug Resistance ,Neoplasm ,Female ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Phosphatidylinositol 3-Kinases ,TOR Serine-Threonine Kinases ,Molecular Targeted Therapy ,Alpelisib ,Palbociclib ,Translational ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
BackgroundCombined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/HER2- breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance.MethodsIn this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance.ResultsWe show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2- breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2- breast cancer models.ConclusionsThese data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2- breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.
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- 2020
22. Potent Cell-Cycle Inhibition and Upregulation of Immune Response with Abemaciclib and Anastrozole in neoMONARCH, Phase II Neoadjuvant Study in HR+/HER2− Breast Cancer
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Hurvitz, Sara A, Martin, Miguel, Press, Michael F, Chan, David, Fernandez-Abad, María, Petru, Edgar, Rostorfer, Regan, Guarneri, Valentina, Huang, Chiun-Sheng, Barriga, Susana, Wijayawardana, Sameera, Brahmachary, Manisha, Ebert, Philip J, Hossain, Anwar, Liu, Jiangang, Abel, Adam, Aggarwal, Amit, Jansen, Valerie M, and Slamon, Dennis J
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Clinical Research ,Clinical Trials and Supportive Activities ,Breast Cancer ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adaptive Immunity ,Adult ,Aged ,Aged ,80 and over ,Aminopyridines ,Anastrozole ,Antineoplastic Combined Chemotherapy Protocols ,Benzimidazoles ,Breast Neoplasms ,Cell Cycle Checkpoints ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Estrogen Receptor alpha ,Female ,Humans ,Middle Aged ,Neoadjuvant Therapy ,Neoplasm Staging ,Patient Safety ,Postmenopause ,Receptor ,ErbB-2 ,Receptors ,Progesterone ,Treatment Outcome ,Receptor ,erbB-2 ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeneoMONARCH assessed the biological effects of abemaciclib in combination with anastrozole in the neoadjuvant setting.Patients and methodsPostmenopausal women with stage I-IIIB HR+/HER2- breast cancer were randomized to a 2-week lead-in of abemaciclib, anastrozole, or abemaciclib plus anastrozole followed by 14 weeks of the combination. The primary objective evaluated change in Ki67 from baseline to 2 weeks of treatment. Additional objectives included clinical, radiologic, and pathologic responses, safety, as well as gene expression changes related to cell proliferation and immune response.ResultsAbemaciclib, alone or in combination with anastrozole, achieved a significant decrease in Ki67 expression and led to potent cell-cycle arrest after 2 weeks of treatment compared with anastrozole alone. More patients in the abemaciclib-containing arms versus anastrozole alone achieved complete cell-cycle arrest (58%/68% vs. 14%, P < 0.001). At the end of treatment, following 2 weeks lead-in and 14 weeks of combination therapy, 46% of intent-to-treat patients achieved a radiologic response, with pathologic complete response observed in 4%. The most common all-grade adverse events were diarrhea (62%), constipation (44%), and nausea (42%). Abemaciclib, anastrozole, and the combination inhibited cell-cycle processes and estrogen signaling; however, combination therapy resulted in increased cytokine signaling and adaptive immune response indicative of enhanced antigen presentation and activated T-cell phenotypes.ConclusionsAbemaciclib plus anastrozole demonstrated biological and clinical activity with generally manageable toxicities in patients with HR+/HER2- early breast cancer. Abemaciclib led to potent cell-cycle arrest, and in combination with anastrozole, enhanced immune activation.
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- 2020
23. CDK6 is upregulated and may be a potential therapeutic target in enzalutamide-resistant castration-resistant prostate cancer
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Xi Chen, Yechen Wu, Xinan Wang, Chengdang Xu, Licheng Wang, Jingang Jian, Denglong Wu, and Gang Wu
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Differentially expressed genes ,Castration-resistant prostate cancer ,Enzalutamide ,Hub gene ,Cyclin-dependent kinase 6 ,Therapeutic target ,Medicine - Abstract
Abstract Background Androgen deprivation therapy (ADT) is still the first-line treatment of prostate cancer (PCa). However, after a certain period of therapy, primary PCa inevitably progresses into castration-resistant PCa (CRPC). Enzalutamide (Enz) is an androgen receptor (AR) signal inhibitor which can delay the progression of CRPC and increase survival of patients with metastatic CRPC. However, the mechanisms involved in enzalutamide-resistant (EnzR) CRPC are still controversial. In the study, we used bioinformatic methods to find potential genes that correlated with the occurrence of EnzR CRPC. Methods We collected RNA sequencing data of the EnzR CRPC cell line LNCaP (EnzR LNCaP) from GSE44905, GSE78201, and GSE150807. We found the hub genes from the three datasets. Then we tested the expression of the hub genes in different databases and the potential drugs that can affect the hub genes. Finally, we verified the hub gene expression and drug function. Results From GSE44905, GSE78201 and GSE150807, we found 45 differentially expressed genes (DEGs) between LNCaP and EnzR LNCaP. Ten hub genes were found in the protein–protein interaction (PPI) network. The expression of hub gene and survival analysis were analyzed by different databases. We found that cyclin-dependent kinase 6 (CDK6) was highly expressed in both the EnzR LNCaP cell and PCa patients. Ten potential small molecules could suppress CDK6 expression as per “CLUE COMMAND” findings. Finally, we found the expression of CDK6 increased in both PCa patients’ samples, CRPC and EnzR PCa cell lines. Three potential CDK6 inhibitors, namely apigenin, chrysin and fisetin, can decrease cell proliferation. Conclusions The study proved that the abnormal overexpression of CDK6 may be a reason behind EnzR CRPC occurrence and suppression CDK6 expression may help treat EnzR CRPC.
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- 2022
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24. Clinical Implications and Treatment Strategies for ESR1 Fusions in Hormone Receptor-Positive Metastatic Breast Cancer: A Case Series.
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Brett, Jamie O, Ritterhouse, Lauren L, Newman, Erik T, Irwin, Kelly E, Dawson, Megan, Ryan, Lianne Y, Spring, Laura M, Rivera, Miguel N, Lennerz, Jochen K, Dias-Santagata, Dora, Ellisen, Leif W, Bardia, Aditya, and Wander, Seth A
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GENETIC mutation ,METASTASIS ,GENETIC testing ,ESTROGEN receptors ,CYCLIN-dependent kinases ,AROMATASE inhibitors ,GENE rearrangement ,HORMONE receptor positive breast cancer ,DRUG resistance in cancer cells - Abstract
In hormone receptor-positive metastatic breast cancer (HR+ MBC), endocrine resistance is commonly due to genetic alterations of ESR1, the gene encoding estrogen receptor alpha (ERα). While ESR1 point mutations (ESR1-MUT) cause acquired resistance to aromatase inhibition (AI) through constitutive activation, far less is known about the molecular functions and clinical consequences of ESR1 fusions (ESR1-FUS). This case series discusses 4 patients with HR+ MBC with ESR1-FUS in the context of the existing ESR1-FUS literature. We consider therapeutic strategies and raise the hypothesis that CDK4/6 inhibition (CDK4/6i) may be effective against ESR1-FUS with functional ligand-binding domain swaps. These cases highlight the importance of screening for ESR1-FUS in patients with HR+ MBC while continuing investigation of precision treatments for these genomic rearrangements. Little is known about the molecular functions and clinical consequences of ESR1 fusions. This case series discusses 4 patients with HR+ metastatic breast cancer with ESR1 fusions in the context of the existing literature. [ABSTRACT FROM AUTHOR]
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- 2023
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25. Cyclin D-Cdk4,6 Drives Cell-Cycle Progression via the Retinoblastoma Protein’s C-Terminal Helix
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Topacio, Benjamin R, Zatulovskiy, Evgeny, Cristea, Sandra, Xie, Shicong, Tambo, Carrie S, Rubin, Seth M, Sage, Julien, Kõivomägi, Mardo, and Skotheim, Jan M
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Biochemistry and Cell Biology ,Biological Sciences ,Cancer ,Cell Cycle ,Cell Proliferation ,Crk-Associated Substrate Protein ,Cyclin D ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Cyclins ,G1 Phase ,Humans ,Molecular Docking Simulation ,Phosphorylation ,Protein Binding ,Protein Conformation ,alpha-Helical ,Protein Interaction Maps ,Retinoblastoma Protein ,Retinoblastoma-Like Protein p107 ,S Phase ,Cdk ,E2F ,G1/S ,Rb ,cell-cycle regulation ,cyclin ,docking ,kinase ,phosphorylation ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
The cyclin-dependent kinases Cdk4 and Cdk6 form complexes with D-type cyclins to drive cell proliferation. A well-known target of cyclin D-Cdk4,6 is the retinoblastoma protein Rb, which inhibits cell-cycle progression until its inactivation by phosphorylation. However, the role of Rb phosphorylation by cyclin D-Cdk4,6 in cell-cycle progression is unclear because Rb can be phosphorylated by other cyclin-Cdks, and cyclin D-Cdk4,6 has other targets involved in cell division. Here, we show that cyclin D-Cdk4,6 docks one side of an alpha-helix in the Rb C terminus, which is not recognized by cyclins E, A, and B. This helix-based docking mechanism is shared by the p107 and p130 Rb-family members across metazoans. Mutation of the Rb C-terminal helix prevents its phosphorylation, promotes G1 arrest, and enhances Rb's tumor suppressive function. Our work conclusively demonstrates that the cyclin D-Rb interaction drives cell division and expands the diversity of known cyclin-based protein docking mechanisms.
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- 2019
26. Obatoclax, a BH3 Mimetic, Enhances Cisplatin-Induced Apoptosis and Decreases the Clonogenicity of Muscle Invasive Bladder Cancer Cells via Mechanisms That Involve the Inhibition of Pro-Survival Molecules as Well as Cell Cycle Regulators.
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Steele, Thomas M, Talbott, George C, Sam, Anhao, Tepper, Clifford G, Ghosh, Paramita M, and Vinall, Ruth L
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Cell Line ,Tumor ,Humans ,Neoplasm Invasiveness ,Cisplatin ,Pyrroles ,Cyclin D1 ,Proto-Oncogene Proteins c-bcl-2 ,Cell Proliferation ,Cell Survival ,Gene Expression Regulation ,Neoplastic ,Dose-Response Relationship ,Drug ,Drug Synergism ,bcl-X Protein ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Urinary Bladder ,Urinary Bladder Neoplasms ,BH3 mimetics ,Obatoclax ,apoptosis ,bladder cancer ,cisplatin ,Cell Line ,Tumor ,Gene Expression Regulation ,Neoplastic ,Dose-Response Relationship ,Drug ,Other Chemical Sciences ,Genetics ,Other Biological Sciences ,Chemical Physics - Abstract
Several studies by our group and others have determined that expression levels of Bcl-2 and/or Bcl-xL, pro-survival molecules which are associated with chemoresistance, are elevated in patients with muscle invasive bladder cancer (MI-BC). The goal of this study was to determine whether combining Obatoclax, a BH3 mimetic which inhibits pro-survival Bcl-2 family members, can improve responses to cisplatin chemotherapy, the standard of care treatment for MI-BC. Three MI-BC cell lines (T24, TCCSuP, 5637) were treated with Obatoclax alone or in combination with cisplatin and/or pre-miR-34a, a molecule which we have previously shown to inhibit MI-BC cell proliferation via decreasing Cdk6 expression. Proliferation, clonogenic, and apoptosis assays confirmed that Obatoclax can decrease cell proliferation and promote apoptosis in a dose-dependent manner. Combination treatment experiments identified Obatoclax + cisplatin as the most effective treatment. Immunoprecipitation and Western analyses indicate that, in addition to being able to inhibit Bcl-2 and Bcl-xL, Obatoclax can also decrease cyclin D1 and Cdk4/6 expression levels. This has not previously been reported. The combined data demonstrate that Obatoclax can inhibit cell proliferation, promote apoptosis, and significantly enhance the effectiveness of cisplatin in MI-BC cells via mechanisms that likely involve the inhibition of both pro-survival molecules and cell cycle regulators.
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- 2019
27. Combined CDK4/6 and Pan-mTOR Inhibition Is Synergistic Against Intrahepatic Cholangiocarcinoma
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Song, Xinhua, Liu, Xianqiong, Wang, Haichuan, Wang, Jingxiao, Qiao, Yu, Cigliano, Antonio, Utpatel, Kirsten, Ribback, Silvia, Pilo, Maria G, Serra, Marina, Gordan, John D, Che, Li, Zhang, Shanshan, Cossu, Antonio, Porcu, Alberto, Pascale, Rosa M, Dombrowski, Frank, Hu, Hongbo, Calvisi, Diego F, Evert, Matthias, and Chen, Xin
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Digestive Diseases - (Gallbladder) ,Rare Diseases ,Orphan Drug ,Prevention ,Liver Cancer ,Digestive Diseases ,Cancer ,Liver Disease ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Animals ,Antineoplastic Combined Chemotherapy Protocols ,Apoptosis ,Benzoxazoles ,Cell Line ,Tumor ,Cell Proliferation ,Cholangiocarcinoma ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Heterografts ,Humans ,Mice ,Phosphorylation ,Piperazines ,Protein Kinase Inhibitors ,Pyridines ,Pyrimidines ,TOR Serine-Threonine Kinases ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeIntrahepatic cholangiocarcinoma (ICC) is an aggressive cancer type, lacking effective therapies and associated with a dismal prognosis. Palbociclib is a selective CDK4/6 inhibitor, which has been shown to suppress cell proliferation in many experimental cancer models. Recently, we demonstrated that pan-mTOR inhibitors, such as MLN0128, effectively induce apoptosis, although have limited efficacy in restraining proliferation of ICC cells. Here, we tested the hypothesis that palbociclib, due to its antproliferative properties in many cancer types, might synergize with MLN0128 to impair ICC growth.Experimental designHuman ICC cell lines and the AKT/YapS127A ICC mouse model were used to test the therapeutic efficacy of palbociclib and MLN0128, either alone or in combination.ResultsAdministration of palbociclib suppressed in vitro ICC cell growth by inhibiting cell-cycle progression. Concomitant administration of palbociclib and MLN0128 led to a pronounced, synergistic growth constraint of ICC cell lines. Furthermore, while treatment with palbociclib or MLN0128 alone resulted in tumor growth reduction in AKT/YapS127A mice, a remarkable tumor regression was achieved when the two drugs were administered simultaneously. Mechanistically, palbociclib was found to potentiate MLN0128 mTOR inhibition activity, whereas MLN0128 prevented the upregulation of cyclin D1 induced by palbociclib treatment.ConclusionsOur study indicates the synergistic activity of palbociclib and MLN0128 in inhibiting ICC cell proliferation. Thus, combination of CDK4/6 and mTOR inhibitors might represent a novel, promising, and effective therapeutic approach against human ICC.See related commentary by Malumbres, p. 6.
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- 2019
28. Radiotherapy and CDK inhibitors: Opportunities and risks.
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Brion, T. and Quéro, L.
- Abstract
CDK4/6 inhibitors are nowadays commonly used in metastatic HR+/HER2− breast cancer. Herein, we report a literature review regarding the benefits and risks of their combination with radiotherapy. Numerous pre-clinical studies have indeed shown a potential synergistic effect of these treatments in combination with radiotherapy in various types of cancers. On the other hand, some retrospective clinical studies have reported increased acute toxicity in case of digestive or pulmonary irradiation; therefore, it is advisable to discontinue CDK4/6 inhibitors before starting irradiation. Several prospective clinical trials are currently ongoing to assess the feasibility of this combination. [ABSTRACT FROM AUTHOR]
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- 2022
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29. Hedgehog signaling drives medulloblastoma growth via CDK6
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Raleigh, David R, Choksi, Pervinder K, Krup, Alexis Leigh, Mayer, Wasima, Santos, Nicole, and Reiter, Jeremy F
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Biotechnology ,Brain Cancer ,Pediatric ,Genetics ,Brain Disorders ,Pediatric Research Initiative ,Human Genome ,Pediatric Cancer ,Rare Diseases ,Neurosciences ,Animals ,Cell Line ,Tumor ,Cell Proliferation ,Cell Survival ,Cerebellar Neoplasms ,Cyclin-Dependent Kinase 6 ,Female ,Hedgehog Proteins ,Humans ,Medulloblastoma ,Mice ,Neoplasm Proteins ,Nuclear Proteins ,Signal Transduction ,Zinc Finger Protein Gli2 ,Brain cancer ,Oncology ,Therapeutics ,Medical and Health Sciences ,Immunology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Medulloblastoma, an aggressive cancer of the cerebellum, is among the most common pediatric brain tumors. Approximately one-third of medulloblastomas are associated with misactivation of the Hedgehog (Hh) pathway. GLI family zinc finger 2 (GLI2) coordinates the Hh transcriptional program; however, the GLI2 targets that promote cancer cell proliferation are unknown. Here, we incorporated a Gli2-EGFP allele into 2 different genetic mouse models of Hh-associated medulloblastoma. Hh signaling induced GLI2 binding to the Cdk6 promoter and activated Cdk6 expression, thereby promoting uncontrolled cell proliferation. Genetic or pharmacological inhibition of CDK6 in mice repressed the growth of Hh-associated medulloblastoma and prolonged survival through inhibition of cell proliferation. In human medulloblastoma, misactivation of Hh signaling was associated with high levels of CDK6, pointing to CDK6 as a direct transcriptional target of the Hh pathway. These results suggest that CDK6 antagonists may be a promising therapeutic approach for Hh-associated medulloblastoma in humans.
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- 2018
30. MicroRNA‐206 prevents the pathogenesis of hepatocellular carcinoma by modulating expression of met proto‐oncogene and cyclin‐dependent kinase 6 in mice
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Wu, Heng, Tao, Junyan, Li, Xiaolei, Zhang, Tianpeng, Zhao, Lei, Wang, Yao, Zhang, Lei, Xiong, Jun, Zeng, Zhi, Zhan, Na, Steer, Clifford J, Che, Li, Dong, Mingjie, Wang, Xiaomei, Niu, Junqi, Li, Zhuoyu, Yan, Guiqing, Chen, Xin, and Song, Guisheng
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Rare Diseases ,Orphan Drug ,Liver Disease ,Cancer ,Digestive Diseases ,Prevention ,Liver Cancer ,Biotechnology ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Base Sequence ,Carcinoma ,Hepatocellular ,Cell Line ,Tumor ,Cyclin D1 ,Cyclin-Dependent Kinase 6 ,Genes ,myc ,Humans ,Liver ,Liver Neoplasms ,Experimental ,Male ,Mice ,Inbred BALB C ,Mice ,Nude ,MicroRNAs ,Proto-Oncogene Mas ,Proto-Oncogene Proteins c-akt ,Proto-Oncogene Proteins c-met ,Xenograft Model Antitumor Assays ,ras Proteins ,Medical Biochemistry and Metabolomics ,Clinical Sciences ,Immunology ,Gastroenterology & Hepatology - Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and therapeutic agents for this malignancy are lacking. MicroRNAs play critical roles in carcinogenesis and present tremendous therapeutic potential. Here, we report that microRNA-206 is a robust tumor suppressor that plays important roles in the development of HCC by regulating cell-cycle progression and the cMet signaling pathway. MicroRNA-206 was underexpressed in livers of two HCC mouse models, human individuals bearing HCC, and human HCC cell lines. Combining bioinformatic prediction and molecular and cellular approaches, we identified cMET (Met proto-oncogene), cyclin D1 (CCND1), and cyclin-dependent kinase 6 (CDK6) as functional targets of microRNA-206. By inhibiting expression of cMET, CCND1, and CDK6, microRNA-206 delayed cell-cycle progression, induced apoptosis, and impaired proliferation of three distinct human HCC cell lines. Systemic administration of microRNA-206 completely prevented HCC development in both cMyc and V-Akt murine thymoma viral oncogene homolog 1/neuroblastoma RAS viral oncogene homolog (AKT/Ras) HCC mice, whereas 100% of control mice died from lethal tumor burdens. Conversely, reintroduction of cMet or Cdk6 into livers of cMyc and AKT/Ras HCC mice recovered growth of HCC inhibited by microRNA-206. These results strongly suggested that cMet and Cdk6 were two functional targets that mediated the inhibitory effect of microRNA-206 on the development of HCC. MicroRNA-206 overexpression demonstrated a profound therapeutic effect on HCC in xenograft and cMyc HCC mice.ConclusionIn summary, this study defines a potentially critical role of microRNA-206 in preventing the growth of HCC and suggests its use as a potential therapeutic strategy for this malignancy. (Hepatology 2017;66:1952-1967).
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- 2017
31. A kinase-independent function of cyclin-dependent kinase 6 promotes outer radial glia expansion and neocortical folding.
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Lei Wang, Jun Young Park, Fengming Liu, Olesen, Kris M., Shirui Hou, Peng, Jamy C., Infield, Jordan, Levesque, Anna C., Yong-Dong Wang, Hongjian Jin, Yiping Fan, Connelly, Patrick J., Pruett-Miller, Shondra M., Miaofen G. Hu, Hinds, Philip W., and Young-Goo Han
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HEDGEHOG signaling proteins , *ENDANGERED species , *PROGENITOR cells , *NEURAL development , *NEOCORTEX - Abstract
The neocortex, the center for higher brain function, first emerged in mammals and has become massively expanded and folded in humans, constituting almost half the volume of the human brain. Primary microcephaly, a developmental disorder in which the brain is smaller than normal at birth, results mainly from there being fewer neurons in the neocortex because of defects in neural progenitor cells (NPCs). Outer radial glia (oRGs), NPCs that are abundant in gyrencephalic species but rare in lissencephalic species, are thought to play key roles in the expansion and folding of the neocortex. However, how oRGs expand, whether they are necessary for neocortical folding, and whether defects in oRGs cause microcephaly remain important questions in the study of brain development, evolution, and disease. Here, we show that oRG expansion in mice, ferrets, and human cerebral organoids requires cyclin-dependent kinase 6 (CDK6), the mutation of which causes primary microcephaly via an unknown mechanism. In a mouse model in which increased Hedgehog signaling expands oRGs and intermediate progenitor cells and induces neocortical folding, CDK6 loss selectively decreased oRGs and abolished neocortical folding. Remarkably, this function of CDK6 in oRG expansion did not require its kinase activity, was not shared by the highly similar CDK4 and CDK2, and was disrupted by the mutation causing microcephaly. Therefore, our results indicate that CDK6 is conserved to promote oRG expansion, that oRGs are necessary for neocortical folding, and that defects in oRG expansion may cause primary microcephaly. [ABSTRACT FROM AUTHOR]
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- 2022
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32. CDK6 is upregulated and may be a potential therapeutic target in enzalutamide-resistant castration-resistant prostate cancer.
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Chen, Xi, Wu, Yechen, Wang, Xinan, Xu, Chengdang, Wang, Licheng, Jian, Jingang, Wu, Denglong, and Wu, Gang
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CASTRATION-resistant prostate cancer ,ANDROGEN deprivation therapy ,SMALL molecules ,ANDROGEN receptors ,GENE expression - Abstract
Background: Androgen deprivation therapy (ADT) is still the first-line treatment of prostate cancer (PCa). However, after a certain period of therapy, primary PCa inevitably progresses into castration-resistant PCa (CRPC). Enzalutamide (Enz) is an androgen receptor (AR) signal inhibitor which can delay the progression of CRPC and increase survival of patients with metastatic CRPC. However, the mechanisms involved in enzalutamide-resistant (EnzR) CRPC are still controversial. In the study, we used bioinformatic methods to find potential genes that correlated with the occurrence of EnzR CRPC. Methods: We collected RNA sequencing data of the EnzR CRPC cell line LNCaP (EnzR LNCaP) from GSE44905, GSE78201, and GSE150807. We found the hub genes from the three datasets. Then we tested the expression of the hub genes in different databases and the potential drugs that can affect the hub genes. Finally, we verified the hub gene expression and drug function. Results: From GSE44905, GSE78201 and GSE150807, we found 45 differentially expressed genes (DEGs) between LNCaP and EnzR LNCaP. Ten hub genes were found in the protein–protein interaction (PPI) network. The expression of hub gene and survival analysis were analyzed by different databases. We found that cyclin-dependent kinase 6 (CDK6) was highly expressed in both the EnzR LNCaP cell and PCa patients. Ten potential small molecules could suppress CDK6 expression as per "CLUE COMMAND" findings. Finally, we found the expression of CDK6 increased in both PCa patients' samples, CRPC and EnzR PCa cell lines. Three potential CDK6 inhibitors, namely apigenin, chrysin and fisetin, can decrease cell proliferation. Conclusions: The study proved that the abnormal overexpression of CDK6 may be a reason behind EnzR CRPC occurrence and suppression CDK6 expression may help treat EnzR CRPC. [ABSTRACT FROM AUTHOR]
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- 2022
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33. Comparison of the Effectiveness and Clinical Outcome of Everolimus Followed by CDK4/6 Inhibitors with the Opposite Treatment Sequence in Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer.
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Hyehyun Jeong, Jae Ho Jeong, Jeong Eun Kim, Jin-Hee Ahn, Kyung Hae Jung, and Sung-Bae Kim
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EVEROLIMUS , *METASTATIC breast cancer , *CYCLIN-dependent kinase inhibitors , *EPIDERMAL growth factor receptors , *TREATMENT effectiveness - Abstract
Purpose In hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer (HR+ HER2-MBC), the mainstay treatment options include cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and everolimus (EVE) in combination with endocrine treatment. This study aims to compare the outcomes of the following treatment sequences: CDK4/6i followed by EVE and EVE followed by CDK4/6i. Materials and Methods Data from HR+ HER2- MBC patients treated between January 2014 and November 2020 with both CDK4/6i and EVE were retrospectively analyzed. Results Among the 88 patients included in the study, 51 received CDK4/6i before EVE (C→E group), and 37 received EVE before CDK4/6i (E→C group) with endocrine treatment. More patients in the E→C group had endocrine resistance (13.7% vs. 40.5%), experienced palliative chemotherapy (7.8% vs. 40.5%), and were heavily treated (treated as ≥ 3rd line, 5.9% vs. 40.5%). Median overall survival was 46.8 months in the C→E group and 38.9 months in the E→C group (p=0.151). Median composite progression-free survival (PFS), defined as the time from the start of the preceding regimen to disease progression on the following regimen or death, was 24.8 months in the C→E group vs. 21.8 months in the E→C group (p=0.681). Median PFS2/PFS1 ratio did not differ significantly between groups (0.5 in the C→E group, 0.6 in the E→C group; p=0.775). Ten patients (11.4%) discontinued EVE, and two patients (2.3%) discontinued CDK4/6i during treatment. Conclusion Although the CDK4/6i-based regimen should be considered as an earlier line of treatment, CDK4/6i- and EVE-based treatments can be valid options in circumstances where the other treatment had been already given. [ABSTRACT FROM AUTHOR]
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- 2022
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34. MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR+/HER2− Metastatic Breast Cancer
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Dickler, Maura N, Tolaney, Sara M, Rugo, Hope S, Cortés, Javier, Diéras, Véronique, Patt, Debra, Wildiers, Hans, Hudis, Clifford A, O'Shaughnessy, Joyce, Zamora, Esther, Yardley, Denise A, Frenzel, Martin, Koustenis, Andrew, and Baselga, José
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Clinical Research ,Breast Cancer ,Clinical Trials and Supportive Activities ,Cancer ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adult ,Aged ,Aged ,80 and over ,Aminopyridines ,Benzimidazoles ,Breast Neoplasms ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Disease-Free Survival ,Drug-Related Side Effects and Adverse Reactions ,Female ,Humans ,Middle Aged ,Neoplasm Metastasis ,Prognosis ,Receptor ,ErbB-2 ,Treatment Outcome ,Receptor ,erbB-2 ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Purpose: The phase II MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor-positive (HR+), HER2- metastatic breast cancer (MBC).Experimental Design: MONARCH 1 was a phase II single-arm open-label study. Women with HR+/HER2- MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible. Abemaciclib 200 mg was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity. The primary objective of MONARCH 1 was investigator-assessed objective response rate (ORR). Other endpoints included clinical benefit rate, progression-free survival (PFS), and overall survival (OS).Results: Patients (n = 132) had a median of 3 (range, 1-8) lines of prior systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had ≥3 metastatic sites. At the 12-month final analysis, the primary objective of confirmed objective response rate was 19.7% (95% CI, 13.3-27.5; 15% not excluded); clinical benefit rate (CR+PR+SD≥6 months) was 42.4%, median progression-free survival was 6.0 months, and median overall survival was 17.7 months. The most common treatment-emergent AEs of any grade were diarrhea, fatigue, and nausea; discontinuations due to AEs were infrequent (7.6%).Conclusions: In this poor-prognosis, heavily pretreated population with refractory HR+/HER2- metastatic breast cancer, continuous dosing of single-agent abemaciciclib was well tolerated and exhibited promising clinical activity. Clin Cancer Res; 23(17); 5218-24. ©2017 AACR.
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- 2017
35. Genome-Wide Overexpression Screen Identifies Genes Able to Bypass p16-Mediated Senescence in Melanoma.
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Lee, Won Jae, Škalamera, Dubravka, Dahmer-Heath, Mareike, Shakhbazov, Konstanin, Ranall, Max V, Fox, Carly, Lambie, Duncan, Stevenson, Alexander J, Yaswen, Paul, Gonda, Thomas J, and Gabrielli, Brian
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Cell Line ,Tumor ,Melanocytes ,Humans ,Lentivirus ,Melanoma ,Nevus ,Skin Neoplasms ,DNA-Binding Proteins ,HMGB Proteins ,Oncogene Proteins ,Viral ,Gene Expression Regulation ,Neoplastic ,Gene Library ,Open Reading Frames ,Genetic Vectors ,Genome ,Human ,Cyclin-Dependent Kinase Inhibitor p16 ,Cyclin-Dependent Kinase 6 ,High-Throughput Screening Assays ,HEK293 Cells ,Cell Cycle Checkpoints ,Cellular Senescence ,CDK6 ,high-content imaging ,overexpression screening ,p16 ,senescence - Abstract
Malignant melanomas often arise from nevi, which result from initial oncogene-induced hyperproliferation of melanocytes that are maintained in a CDKN2A/p16-mediated senescent state. Thus, genes that can bypass this senescence barrier are likely to contribute to melanoma development. We have performed a gain-of-function screen of 17,030 lentivirally expressed human open reading frames (ORFs) in a melanoma cell line containing an inducible p16 construct to identify such genes. Genes known to bypass p16-induced senescence arrest, including the human papilloma virus 18 E7 gene ( HPV18E7), and genes such as the p16-binding CDK6 with expected functions, as well as panel of novel genes, were identified, including high-mobility group box (HMGB) proteins. A number of these were further validated in two other models of p16-induced senescence. Tissue immunohistochemistry demonstrated higher levels of CDK6 in primary melanomas compared with normal skin and nevi. Reduction of CDK6 levels drove melanoma cells expressing functional p16 into senescence, demonstrating its contribution to bypass senescence.
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- 2017
36. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers
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Finn, Richard S, Aleshin, Alexey, and Slamon, Dennis J
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Estrogen ,Breast Cancer ,Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Good Health and Well Being ,Animals ,Antineoplastic Combined Chemotherapy Protocols ,Breast Neoplasms ,Clinical Trials as Topic ,Cyclin D1 ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Estrogen Receptor alpha ,Female ,Humans ,Piperazines ,Protein Kinase Inhibitors ,Pyridines ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Despite significant advances in early detection and treatment, breast cancer still remains a major cause of morbidity and mortality for women. Our understanding of the molecular heterogeneity of the disease has significantly expanded over the past decade and the role of cell cycle signaling in both breast cancer oncogenesis and anti-estrogen resistance has gained increasing attention. The mammalian cell cycle is driven by a complex interplay between cyclins and their associated cyclin-dependent kinase (CDK) partners, and dysregulation of this process is one of the hallmarks of cancer. Despite this, initial results with broadly acting CDK inhibitors were largely disappointing. However, recent preclinical and phase I/II clinical studies using a novel, oral, reversible CDK4/6 inhibitor, palbociclib (PD-0332991), have validated the role of CDK4/6 as a potential target in estrogen receptor-positive (ER+) breast cancers. This review highlights our current understanding of CDK signaling in both normal and malignant breast tissues, with special attention placed on recent clinical advances in inhibition of CDK4/6 in ER+ disease.
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- 2016
37. Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth.
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Hashizume, Rintaro, Zhang, Ali, Mueller, Sabine, Prados, Michael D, Lulla, Rishi R, Goldman, Stewart, Saratsis, Amanda M, Mazar, Andrew P, Stegh, Alexander H, Cheng, Shi-Yuan, Horbinski, Craig, Haas-Kogan, Daphne A, Sarkaria, Jann N, Waldman, Todd, and James, C David
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Neurosciences ,Brain Disorders ,Rare Diseases ,Cancer ,Orphan Drug ,Brain Cancer ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Animals ,Antineoplastic Agents ,Brain Neoplasms ,Cell Line ,Tumor ,Cell Proliferation ,Chemoradiotherapy ,Combined Modality Therapy ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,DNA Damage ,DNA Repair ,Female ,Glioblastoma ,Heterografts ,Humans ,Mice ,Inbred BALB C ,Piperazines ,Pyridines ,Retinoblastoma Protein ,Rhabdoid Tumor ,Survival Analysis ,Teratoma ,Xenograft Model Antitumor Assays ,atypical teratoid rhabdoid tumor ,bioluminescence imaging ,glioblastoma ,palbociclib ,xenograft ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundRadiation therapy is the most commonly used postsurgical treatment for primary malignant brain tumors. Consequently, investigating the efficacy of chemotherapeutics combined with radiation for treating malignant brain tumors is of high clinical relevance. In this study, we examined the cyclin-dependent kinase 4/6 inhibitor palbociclib, when used in combination with radiation for treating human atypical teratoid rhabdoid tumor (ATRT) as well as glioblastoma (GBM).MethodsEvaluation of treatment antitumor activity in vitro was based upon results from cell proliferation assays, clonogenicity assays, flow cytometry, and immunocytochemistry for DNA double-strand break repair. Interpretation of treatment antitumor activity in vivo was based upon bioluminescence imaging, animal subject survival analysis, and staining of tumor sections for markers of proliferation and apoptosis.ResultsFor each of the retinoblastoma protein (RB)-proficient tumor models examined (2 ATRTs and 2 GBMs), one or more of the combination therapy regimens significantly (P < .05) outperformed both monotherapies with respect to animal subject survival benefit. Among the combination therapy regimens, concurrent palbociclib and radiation treatment and palbociclib treatment following radiation consistently outperformed the sequence in which radiation followed palbociclib treatment. In vitro investigation revealed that the concurrent use of palbociclib with radiation, as well as palbociclib following radiation, inhibited DNA double-strand break repair and promoted increased tumor cell apoptosis.ConclusionsOur results support further investigation and possible clinical translation of palbociclib as an adjuvant to radiation therapy for patients with malignant brain tumors that retain RB expression.
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- 2016
38. Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor‐Positive/HER2‐Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo‐Controlled, Phase III Study (PALOMA‐3)
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Verma, Sunil, Bartlett, Cynthia Huang, Schnell, Patrick, DeMichele, Angela M, Loi, Sherene, Ro, Jungsil, Colleoni, Marco, Iwata, Hiroji, Harbeck, Nadia, Cristofanilli, Massimo, Zhang, Ke, Thiele, Alexandra, Turner, Nicholas C, and Rugo, Hope S
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Clinical Trials and Supportive Activities ,Breast Cancer ,Patient Safety ,Vaccine Related ,Cancer ,Clinical Research ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Antineoplastic Combined Chemotherapy Protocols ,Breast Neoplasms ,Double-Blind Method ,Estradiol ,Female ,Fulvestrant ,Humans ,Neoplasm Metastasis ,Piperazines ,Pyridines ,Receptor ,ErbB-2 ,Receptors ,Estrogen ,Cyclin-dependent kinase 4 ,Cyclin-dependent kinase 6 ,Palbociclib ,Neutropenia ,Receptor ,erbB-2 ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
BackgroundPalbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Because this is a new target, it is clinically important to understand palbociclib's safety profile to effectively manage toxicity and optimize clinical benefit.Materials and methodsPatients with endocrine-resistant, HR-positive/HER2-negative MBC (n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments at baseline and day 1 of each cycle included blood counts on day 15 for the first 2 cycles. Hematologic toxicity was assessed by using laboratory data.ResultsA total of 517 patients were treated (palbociclib, n = 345; placebo, n = 172); median follow-up was 8.9 months. With palbociclib, neutropenia was the most common grade 3 (55%) and 4 (10%) adverse event; median times to onset and duration of grade ≥3 episodes were 16 and 7 days, respectively. Asian ethnicity and below-median neutrophil counts at baseline were significantly associated with an increased chance of developing grade 3-4 neutropenia with palbociclib. Dose modifications for grade 3-4 neutropenia had no adverse effect on progression-free survival. In the palbociclib arm, febrile neutropenia occurred in 3 (
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- 2016
39. Hsa_circ_0056558 regulates cyclin-dependent kinase 6 by sponging microRNA-1290 to suppress the proliferation and differentiation in ankylosing spondylitis
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Xia Li, Wenjing Zhou, Zhen Li, and Fei Guan
- Subjects
ankylosing spondylitis ,hsa_circ_0056558 ,microrna-1290 ,cyclin-dependent kinase 6 ,pi3k/akt/nf-κb ,Internal medicine ,RC31-1245 - Abstract
The aims of this study was to investigate the influences of hsa_circ_0056558/miR-1290/CDK6 axis in ankylosing spondylitis (AS). The differentially expressed has_circ_0056558 and miR-1290 in AS tissue were analysed based on RNA-seq data and microarray data, respectively. qRT-PCR was performed for detection of relative expression levels of hsa_circ_0056558, miR-1290, CDK6, osteogenic differentiation markers (Runx2 and Osterix) and other inflammatory factors (TNF-α, IL-1β, and IL-6). Western blotting analysis was conducted to test the protein levels of CDK6, osteogenic differentiation markers (Runx2 and Osterix), and PI3K/AKT/NF-κB pathway-associated proteins. CCK8 assay and flow cytometry were conducted to determine cell proliferation and cell apoptotic ability, respectively. Targeted relationships were predicted by bioinformatic analysis and verified by dual-luciferase reporter assay. The differentiation of fibroblast cells was analysed by alkaline phosphatase (ALP) activity assay. Our findings revealed that the expression levels of both circ_0056558 and CDK6 in AS tissue were significantly higher than that in normal samples. Besides, hsa_circ_0056558 could suppress cell proliferation and differentiation by facilitating CDK6 expression and suppressing miR-1290 expression in AS. Over-expression of miR-1290 negatively regulated CDK6 expression to enhance cell proliferation. The protein levels of p-AKT, p-NF-κB p65, and p-IκBα were promoted by hsa_circ_0056558 or CDK6 over-expression while suppressed by miR-1290 up-regulation. In conclusion, our study demonstrated that hsa_circ_0056558 and CDK6 suppressed cell proliferation and differentiation while enhanced cell apoptosis by competitive binding to miR-1290 in AS, which might be possibly achieved by PI3K/AKT/NF-κB pathway, providing us novel therapeutic strategy for AS.
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- 2021
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40. Exploring therapeutic potential of Rutin by investigating its cyclin-dependent kinase 6 inhibitory activity and binding affinity.
- Author
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Yousuf, Mohd, Khan, Shama, Hussain, Afzal, Alajmi, Mohamed F., Shamsi, Anas, Haque, Qazi Mohd Rizwanul, Islam, Asimul, and Hassan, Md Imtaiyaz
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RUTIN , *ISOTHERMAL titration calorimetry , *FLUORESCENCE spectroscopy , *DRUG target , *MOLECULAR docking - Abstract
Cyclin-dependent kinase 6 (CDK6) participates in numerous signalling pathways and regulates various physiological processes. Due to its unique structural features and promising therapeutic potential, CDK6 has emerged as a drug target for designing and developing small-molecule inhibitors for anti-cancer therapeutics and other CDK6-associated diseases. The current study evaluates binding affinity and the inhibitory potential of rutin for CDK6 to develop a proof of concept for rutin as a potent CDK6 inhibitor. Molecular docking and 200 ns all-atom simulations reveal that rutin binds to the active site pocket of CDK6, forming interactions with key residues of the binding pocket. In addition, the CDK6-rutin complex remains stable throughout the simulation trajectory. A high binding constant (K a = 7.6 × 105 M−1) indicates that rutin has a strong affinity for CDK6. Isothermal titration calorimetry has further validated a strong binding of rutin with CDK6 and its spontaneous nature. The kinase activity of CDK6 is significantly inhibited by rutin with an IC 50 value of 3.10 μM. Our findings highlight the significant role of rutin in developing potential therapeutic molecules to manage cancer and CDK6-associated diseases via therapeutic targeting of CDK6. • Molecular docking suggested significant binding affinity of rutin with CDK6 protein. • MD simulation and computed free energy that suggested a stable complex formation between CDK6-rutin. • Rutin showed an appreciable binding affinity with CDK6 through fluorescence spectroscopy. • Thermodynamics parameters obtained via ITC suggested a stable CDK6-rutin complex. • Rutin showed an excellent IC 50 value for CDK6. [ABSTRACT FROM AUTHOR]
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- 2024
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41. Overexpression of miR-138-5p Sensitizes Taxol-Resistant Epithelial Ovarian Cancer Cells through Targeting Cyclin-Dependent Kinase 6.
- Author
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Liang, Man, Li, Qin, Shi, Shuai, Tian, Ya-ning, Feng, Yanhong, Yang, Yongkang, Dong, Miao, Zhang, Jing, and He, Jihong
- Subjects
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OVARIAN epithelial cancer , *CANCER cells , *OVARIAN cancer , *SPINDLE apparatus , *GENETIC overexpression - Abstract
Background: Ovarian cancer, one of the most malignant diseases in female, is associated with poor diagnosis and low 5-year survival rate. Taxol is a widely used chemotherapeutic drug for the treatment of ovarian cancer by targeting the microtubules of the mitotic spindle to induce cancer cell death. However, with the widespread clinical applications of Taxol, a large fraction of ovarian cancer patients developed drug resistance. Results: Here, we report miR-138-5p is significantly downregulated in epithelial ovarian cancer tissues compared with their matched normal ovarian tissues. Overexpression of miR-138-5p effectively sensitized ovarian cancer cells to Taxol. By establishing Taxol-resistant cell line from the epithelial ovarian cancer cell line, HO-8910, we found miR-138-5p was significantly downregulated in Taxol-resistant cells. Furthermore, overexpression of miR-138-5p dramatically overcame the chemoresistance of Taxol-resistant cells. Intriguingly, bioinformatic analysis indicated miR-138-5p had putative binding sites for cyclin-dependent kinase 6 (CDK6). This negative regulation was further verified from epithelial ovarian cancer tissues. Luciferase assay demonstrated miR-138-5p could directly bind to 3′UTR of CDK6. Importantly, silencing CDK6 expression by siRNA successfully increased the sensitivity of both parental and Taxol-resistant ovarian cancer cells. Finally, rescue experiments clearly elucidated restoration of CDK6 in miR-138-5p-overexpressing ovarian cancer cells successfully recovered the Taxol resistance. Conclusion: In summary, these findings suggest important molecular mechanisms for the miR-138-5p-mediated Taxol sensitivity of ovarian cancer via directly targeting CDK6, suggesting miR-138-5p is an effective therapeutic target for the noncoding RNA-based anti-chemoresistance treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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42. Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model.
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Murakami, Takashi, Singh, Arun S, Kiyuna, Tasuku, Dry, Sarah M, Li, Yunfeng, James, Aaron W, Igarashi, Kentaro, Kawaguchi, Kei, DeLong, Jonathan C, Zhang, Yong, Hiroshima, Yukihiko, Russell, Tara, Eckardt, Mark A, Yanagawa, Jane, Federman, Noah, Matsuyama, Ryusei, Chishima, Takashi, Tanaka, Kuniya, Bouvet, Michael, Endo, Itaru, Eilber, Fritz C, and Hoffman, Robert M
- Subjects
Animals ,Humans ,Mice ,Bone Neoplasms ,Imidazoles ,Piperazines ,Pyrazines ,Pyridines ,Doxorubicin ,Receptor ,IGF Type 1 ,RNA-Binding Protein FUS ,Oncogene Proteins ,Fusion ,Xenograft Model Antitumor Assays ,Drug Resistance ,Neoplasm ,Female ,Cyclin-Dependent Kinase Inhibitor p16 ,Cyclin-Dependent Kinase Inhibitor p18 ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Molecular Targeted Therapy ,Sarcoma ,Ewing ,Ewing’s sarcoma ,PDOX ,linsitinib ,palbociclib ,patient-derived orthotopic xenograft ,Ewing's sarcoma ,Pediatric ,Pediatric Research Initiative ,Orphan Drug ,Cancer ,Rare Diseases ,Pediatric Cancer ,Oncology and Carcinogenesis - Abstract
Ewing's sarcoma is a rare and aggressive malignancy. In the present study, tumor from a patient with a Ewing's sarcoma with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion was implanted in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present study was to determine efficacy of cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors on the Ewing's sarcoma PDOX. The PDOX models were randomized into the following groups when tumor volume reached 50 mm3: G1, untreated control; G2, doxorubicin (DOX) (intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, CDK4/6 inhibitor (palbociclib, PD0332991, per oral (p.o.), daily, for 14 days); G4, IGF-1R inhibitor (linsitinib, OSI-906, p.o., daily, for 14 days). Tumor growth was significantly suppressed both in G3 (palbociclib) and in G4 (linsitinib) compared to G1 (untreated control) at all measured time points. In contrast, DOX did not inhibit tumor growth at any time point, which is consistent with the failure of DOX to control tumor growth in the patient. The results of the present study demonstrate the power of the PDOX model to identify effective targeted molecular therapy of a recalcitrant DOX-resistant Ewing's sarcoma with specific genetic alterations. The results of this study suggest the potential of PDOX models for individually-tailored, effective targeted therapy for recalcitrant cancer.
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- 2016
43. CDK6-mediated repression of CD25 is required for induction and maintenance of Notch1-induced T-cell acute lymphoblastic leukemia
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Jena, N, Sheng, J, Hu, JK, Li, W, Zhou, W, Lee, G, Tsichlis, N, Pathak, A, Brown, N, Deshpande, A, Luo, C, Hu, GF, Hinds, PW, Van Etten, RA, and Hu, MG
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Hematology ,Childhood Leukemia ,Stem Cell Research - Nonembryonic - Non-Human ,Pediatric ,Rare Diseases ,Cancer ,Pediatric Cancer ,Stem Cell Research ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Apoptosis ,Carcinogenesis ,Cell Cycle Checkpoints ,Core Binding Factor Alpha 2 Subunit ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Hematopoietic Stem Cells ,Humans ,Interleukin-2 Receptor alpha Subunit ,Mice ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,Receptor ,Notch1 ,Clinical Sciences ,Immunology ,Cardiovascular medicine and haematology ,Clinical sciences ,Oncology and carcinogenesis - Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk subset of acute leukemia, characterized by frequent activation of Notch1 or AKT signaling, where new therapeutic approaches are needed. We showed previously that cyclin-dependent kinase 6 (CDK6) is required for thymic lymphoblastic lymphoma induced by activated AKT. Here, we show CDK6 is required for initiation and maintenance of Notch-induced T-ALL. In a mouse retroviral model, hematopoietic stem/progenitor cells lacking CDK6 protein or expressing kinase-inactive (K43M) CDK6 are resistant to induction of T-ALL by activated Notch, whereas those expressing INK4-insensitive (R31C) CDK6 are permissive. Pharmacologic inhibition of CDK6 kinase induces CD25 and RUNX1 expression, cell cycle arrest and apoptosis in mouse and human T-ALL. Ablation of Cd25 in a K43M background restores Notch-induced T leukemogenesis, with disease that is resistant to CDK6 inhibitors in vivo. These data support a model whereby CDK6-mediated suppression of CD25 is required for initiation of T-ALL by activated Notch1, and CD25 induction mediates the therapeutic response to CDK6 inhibition in established T-ALL. These results both validate CDK6 as a molecular target for therapy of this subset of T-ALL and suggest that CD25 expression could serve as a biomarker for responsiveness of T-ALL to CDK4/6 inhibitor therapy.
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- 2016
44. RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation
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Palanichamy, Jayanth Kumar, Tran, Tiffany M, Howard, Jonathan M, Contreras, Jorge R, Fernando, Thilini R, Sterne-Weiler, Timothy, Katzman, Sol, Toloue, Masoud, Yan, Weihong, Basso, Giuseppe, Pigazzi, Martina, Sanford, Jeremy R, and Rao, Dinesh S
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Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Biological Sciences ,Stem Cell Research ,Orphan Drug ,Hematology ,Pediatric Cancer ,Genetics ,Stem Cell Research - Nonembryonic - Non-Human ,Pediatric ,Cancer ,Rare Diseases ,Aetiology ,1.1 Normal biological development and functioning ,Underpinning research ,2.1 Biological and endogenous factors ,3' Untranslated Regions ,Animals ,B-Lymphocytes ,Cell Line ,Tumor ,Cell Proliferation ,Cyclin-Dependent Kinase 6 ,Female ,Gene Expression Regulation ,Leukemic ,Hematopoietic Stem Cells ,Humans ,Insulin-Like Growth Factor Binding Protein 3 ,Male ,Mice ,Myeloid Cells ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Proto-Oncogene Proteins c-myc ,RNA ,Neoplasm ,RNA-Binding Proteins ,Medical and Health Sciences ,Immunology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Posttranscriptional control of gene expression is important for defining both normal and pathological cellular phenotypes. In vitro, RNA-binding proteins (RBPs) have recently been shown to play important roles in posttranscriptional regulation; however, the contribution of RBPs to cell specification is not well understood. Here, we determined that the RBP insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is specifically overexpressed in mixed lineage leukemia-rearranged (MLL-rearranged) B-acute lymphoblastic leukemia (B-ALL), which constitutes a subtype of this malignancy associated with poor prognosis and high risk of relapse. IGF2BP3 was required for the survival of B-ALL cell lines, as knockdown led to decreased proliferation and increased apoptosis. Enforced expression of IGF2BP3 provided murine BM cells with a strong survival advantage, led to proliferation of hematopoietic stem and progenitor cells, and skewed hematopoietic development to the B cell/myeloid lineage. Cross-link immunoprecipitation and high throughput sequencing uncovered the IGF2BP3-regulated transcriptome, which includes oncogenes MYC and CDK6 as direct targets. IGF2BP3 regulated transcripts via targeting elements within 3' untranslated regions (3'UTR), and enforced IGF2BP3 expression in mice resulted in enhanced expression of Myc and Cdk6 in BM. Together, our data suggest that IGF2BP3-mediated targeting of oncogenic transcripts may represent a critical pathogenetic mechanism in MLL-rearranged B-ALL and support IGF2BP3 and its cognate RNA-binding partners as potential therapeutic targets in this disease.
- Published
- 2016
45. Cyclin-dependent kinase pathways as targets for women's cancer treatment
- Author
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Konecny, Gottfried E
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Brain Cancer ,Brain Disorders ,Orphan Drug ,Breast Cancer ,Rare Diseases ,Ovarian Cancer ,Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Aminopyridines ,Antineoplastic Agents ,Antineoplastic Combined Chemotherapy Protocols ,Breast Neoplasms ,Cell Cycle ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Female ,Humans ,Liposarcoma ,Lymphoma ,Mantle-Cell ,Melanoma ,Neoplasms ,Germ Cell and Embryonal ,Piperazines ,Protein Kinase Inhibitors ,Purines ,Pyridines ,Signal Transduction ,abemaciclib (LY2835219) and ribociclib ,cyclin-dependent kinase 4 and 6 inhibition ,palbociclib ,Paediatrics and Reproductive Medicine ,Obstetrics & Reproductive Medicine ,Reproductive medicine - Abstract
Purpose of reviewIn this article, we not only review the preclinical and clinical studies of cyclin-dependent kinase (CDK) 4/6 inhibitors in breast cancer, liposarcoma, mantel cell lymphoma, melanoma and germ cell tumors, but also examine promising preclinical data in glioblastoma, renal and ovarian cancer models that may provide directions for future development.Recent findingsTargeting CDKs has been the focus of considerable basic science and clinical research. The CDK 4/6 inhibitors are a novel class of therapeutics that target the CDK 4/6 kinases that promote transition through the cell cycle. Currently, palbociclib (PD0332991, Pfizer), abemaciclib (LY2835219, Lilly) and ribociclib (LEE011, Novartis) are being investigated in clinical trials. These oral agents offer the hope of clinical efficacy in many tumor types, and have been associated with minimal toxicity. Amplification/overexpression of cyclin D, loss of CDKN2A (p16) and amplification/overexpression of CDK4 are proposed biomarkers of improved response to CDK4/6 inhibition.SummaryPalbociclib, abemaciclib and ribociclib have demonstrated very promising clinical activity in breast cancer, liposarcoma, mantel cell lymphoma and melanoma. Moreover, CDK4/6 inhibitors have shown promising preclinical activity in glioblastoma, renal and ovarian cancer models that may provide directions for their future clinical development. Further preclinical and clinical research is needed to better understand mechanisms of resistance and develop rational combination therapies with other targeted agents.
- Published
- 2016
46. Cyclin-dependent kinase 7 (CDK7) inhibitors as a novel therapeutic strategy for different molecular types of breast cancer.
- Author
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Song X, Fang C, Dai Y, Sun Y, Qiu C, Lin X, and Xu R
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- Humans, Female, Cyclin-Dependent Kinases metabolism, Cyclin-Dependent Kinases therapeutic use, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms metabolism, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms genetics
- Abstract
Background: Cyclin-dependent kinase (CDK) 7 is aberrantly overexpressed in many types of cancer and is an attractive target for cancer therapy due to its dual role in transcription and cell cycle progression. Moreover, CDK7 can directly modulate the activities of estrogen receptor (ER), which is a major driver in breast cancer. Breast cancer cells have exhibited high sensitivity to CDK7 inhibition in pre-clinical studies., Methods: In this review, we provide a comprehensive summary of the latest insights into CDK7 biology and recent advancements in CDK7 inhibitor development for breast cancer treatment. We also discuss the current application of CDK7 inhibitors in different molecular types of breast cancer to provide potential strategies for the treatment of breast cancer., Results: Significant progress has been made in the development of selective CDK7 inhibitors, which show efficacy in both triple-negative breast cancer (TNBC) and hormone receptor-positive breast cancer (HR+). Moreover, combined with other agents, CDK7 inhibitors may provide synergistic effects for endocrine therapy and chemotherapy. Thus, high-quality studies for developing potent CDK7 inhibitors and investigating their applications in breast cancer therapy are rapidly emerging., Conclusion: CDK7 inhibitors have emerged as a promising therapeutic strategy and have demonstrated significant anti-cancer activity in different subtypes of breast cancer, especially those that have been resistant to current therapies., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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47. CD63 + cancer-associated fibroblasts confer CDK4/6 inhibitor resistance to breast cancer cells by exosomal miR-20.
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Sun J, Du R, Li X, Liu C, Wang D, He X, Li G, Zhang K, Wang S, Hao Q, Zhang Y, Li M, Gao Y, and Zhang C
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- Humans, Female, Cyclin-Dependent Kinase 4, Cell Proliferation, Cyclin-Dependent Kinase 6, Tumor Microenvironment, Tetraspanin 30 metabolism, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology, Cancer-Associated Fibroblasts metabolism, MicroRNAs metabolism
- Abstract
Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) have rapidly received Food and Drug Administration (FDA) approval as a new type of therapy for patients with advanced hormone receptor-positive breast cancer. However, with the widespread application of CDK4/6i, drug resistance has become a new challenge for clinical practice and has greatly limited the treatment effect. Here, the whole microenvironment landscape of ER
+ breast cancer tumors was revealed through single-cell RNA sequencing, and a specific subset of cancer-associated fibroblasts (CD63+ CAFs) was identified as highly enriched in CDK4/6i resistant tumor tissues. Then, we found that CD63+ CAFs can distinctly promote resistance to CDK4/6i in breast cancer cells and tumor xenografts. In addition, it was discovered that miR-20 is markedly enriched in the CD63+ CAFs-derived exosomes, which are used to communicate with ER+ breast cancer cells, leading to CDK4/6i resistance. Furthermore, exosomal miR-20 could directly target the RB1 mRNA 3'UTR and negatively regulate RB1 expression to decrease CDK4/6i sensitivity in breast cancer cells. Most importantly, we designed and synthesized cRGD-miR-20 sponge nanoparticles and found that they can enhance the therapeutic effect of CDK4/6i in breast cancer. In summary, our findings reveal that CD63+ CAFs can promote CDK4/6i resistance via exosomal miR-20, which induces the downregulation of RB1 in breast cancer cells, and suggest that CD63+ CAFs may be a novel therapeutic target to enhance CDK4/6i sensitivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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48. Cotargeting CDK4/6 and BRD4 Promotes Senescence and Ferroptosis Sensitivity in Cancer.
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Zhu X, Fu Z, Dutchak K, Arabzadeh A, Milette S, Steinberger J, Morin G, Monast A, Pilon V, Kong T, Adams BN, Prando Munhoz E, Hosein HJB, Fang T, Su J, Xue Y, Rayes R, Sangwan V, Walsh LA, Chen G, Quail DF, Spicer JD, Park M, Dankort D, and Huang S
- Subjects
- Animals, Mice, Cyclin-Dependent Kinase 4, Nuclear Proteins metabolism, Proto-Oncogene Proteins p21(ras) metabolism, Reactive Oxygen Species metabolism, Cell Line, Tumor, Transcription Factors metabolism, Cyclin-Dependent Kinase 6, Protein Kinase Inhibitors pharmacology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Cytostatic Agents therapeutic use, Ferroptosis, Lung Neoplasms genetics
- Abstract
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are approved for breast cancer treatment and show activity against other malignancies, including KRAS-mutant non-small cell lung cancer (NSCLC). However, the clinical efficacy of CDK4/6 inhibitors is limited due to frequent drug resistance and their largely cytostatic effects. Through a genome-wide cDNA screen, we identified that bromodomain-containing protein 4 (BRD4) overexpression conferred resistance to the CDK4/6 inhibitor palbociclib in KRAS-mutant NSCLC cells. Inhibition of BRD4, either by RNA interference or small-molecule inhibitors, synergized with palbociclib to induce senescence in NSCLC cells and tumors, and the combination prolonged survival in a KRAS-mutant NSCLC mouse model. Mechanistically, BRD4-inhibition enhanced cell-cycle arrest and reactive oxygen species (ROS) accumulation, both of which are necessary for senescence induction; this in turn elevated GPX4, a peroxidase that suppresses ROS-triggered ferroptosis. Consequently, GPX4 inhibitor treatment selectively induced ferroptotic cell death in the senescent cancer cells, resulting in tumor regression. Cotargeting CDK4/6 and BRD4 also promoted senescence and ferroptosis vulnerability in pancreatic and breast cancer cells. Together, these findings reveal therapeutic vulnerabilities and effective combinations to enhance the clinical utility of CDK4/6 inhibitors., Significance: The combination of cytostatic CDK4/6 and BRD4 inhibitors induces senescent cancer cells that are primed for activation of ferroptotic cell death by targeting GPX4, providing an effective strategy for treating cancer., (©2024 American Association for Cancer Research.)
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- 2024
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49. Cyclin-dependent kinase 2 (CDK2) inhibitors and others novel CDK inhibitors (CDKi) in breast cancer: clinical trials, current impact, and future directions.
- Author
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Gerosa R, De Sanctis R, Jacobs F, Benvenuti C, Gaudio M, Saltalamacchia G, Torrisi R, Masci G, Miggiano C, Agustoni F, Pedrazzoli P, Santoro A, and Zambelli A
- Subjects
- Humans, Female, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase 4, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Cell Cycle Checkpoints, Cyclin-Dependent Kinase 6, Breast Neoplasms pathology, Triple Negative Breast Neoplasms drug therapy
- Abstract
Aberrant cyclin-dependent kinase 2 (CDK2) activation has been identified as a main resistance mechanism to CDK4/6 inhibition in hormone-receptor positive (HR+) breast cancer. Additionally, consistent preclinical evidence states its crucial role in MYC and CCNE1 overexpressed cancer survival, such as triple-negative breast cancers (TNBC), thus representing an appealing and relatively unexplored target treatment opportunity. Despite emerging initial results of novel CDK2 inhibitors (CDK2i) activity, a comprehensive outcomes collection is currently absent from the scientific literature. We aim to provide an overview of ongoing clinical trials involving CDK2i in the context of metastatic breast cancer (mBC), either as monotherapy or in combination with other agents. The review extends beyond CDK2i to encompass novel emerging CDK4 inhibitors, combined CDK2/4/6 inhibitors, and the well-known pan-CDK inhibitors including those specifically directed at CDK2. Delving into the results, we critically appraise the observed clinical efficacy and offer valuable insights into their potential impact and future applications., Competing Interests: Declaration of Competing Interest Armando Santoro: Advisory Board: Bristol-Myers Squibb (BMS), Servier, Gilead, Pfizer, Eisai, Bayer, Merck Sharp & Dohme (MSD). Consultancy: Arqule, Sanofi, Incyte. Speaker’s Bureau: Takeda, BMS, Roche, Abb-Vie, Amgen, Celgene, Servier, Gilead, Astrazeneca, Pfizer, Arqule, Lilly, Sandoz, Eisai, Novartis, Bayer, MSD (all outside the submitted work); Alberto Zambelli has received personal fees and non-financial support from Novartis, AstraZeneca, Lilly, Pfizer, Daiichi Sankyo, MDS Merck Sharp&Dome, Roche, Seagen, Exact Sciences, Gilaed, Istituto Gentili; Rosalba Torrisi has received funding from Astra Zeneca, Pfizer, Eli Lilly, Exact Sciences and MSD; Rita De Sanctis honoraria for advisory board consultancy from Novartis, Istituto Clinico Gentili, Amgen, EISAI, Lilly and Gilead (all outside the present work). The other authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)
- Published
- 2024
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50. Cardiovascular complications of ribociclib in breast cancer patients.
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Fiste O, Mavrothalassitis E, Apostolidou K, Trika C, Liontos M, Koutsoukos K, Kaparelou M, Dimitrakakis C, Gavriatopoulou M, Dimopoulos MA, and Zagouri F
- Subjects
- Female, Humans, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Protein Kinase Inhibitors therapeutic use, Quality of Life, Receptor, ErbB-2, Clinical Trials as Topic, Aminopyridines, Breast Neoplasms complications, Breast Neoplasms drug therapy, Purines
- Abstract
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have unprecedentedly advanced hormone-dependent breast cancer treatment paradigm. In the metastatic setting, ribociclib has consistently demonstrated survival benefit in pre-, peri-, and postmenopausal patients, conjugating efficacy with health-related quality of life preservation. Accordingly, the emergence of cardiac and/or vascular adverse events related to this novel targeted agent is gaining significant interest. This narrative review provides an overview of the incidence and spectrum of cardiovascular toxicity, in both clinical trial framework and real-world evidence. The potential pathogenetic mechanism, along with the available diagnostic parameters including biomarkers, and proper management, are also summarized., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
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