7,946 results on '"Cyclin-dependent kinase 4"'
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. Case report: Atypical lipomatous tumor of the thigh in a four-year-old girl.
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Itaru Ogawa, Michiyuki Hakozaki, Yoichi Kaneuchi, Takeo Suzuki, Takuya Nikaido, Shoki Yamada, Akihito Utsumi, Osamu Hasegawa, Hideki Sano, and Yoshihiro Matsumoto
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TUMORS in children ,FLUORESCENCE in situ hybridization ,PLEOMORPHIC adenoma ,MIDDLE-aged persons ,GENE amplification - Abstract
Atypical lipomatous tumors (ALTs) are locally aggressive adipocytic malignancies that frequently occur in middle-aged adults. We report the rare case of an ALT of the thigh that occurred in a 4-year-old girl. Since the tumor was initially diagnosed as a lipoblastoma by incisional biopsy, marginal resection was performed. Histopathological findings of the surgical specimen revealed the proliferation of mature and variously sized adipocytes, as well as ectopic ossification; these features differ from the typical findings of lipoblastoma. Immunohistochemical findings showed nuclear positivity for a murine double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) and negativity for pleomorphic adenoma gene 1 (PLAG1). Fluorescence in situ hybridization showed abnormal amplification of the MDM2 gene. The patient was thus finally diagnosed as having an ALT. No signs of local recurrence or metastasis were noted 1 year postoperatively. This case is instructive in the differential diagnosis of primary adipocytic tumors. Lipoblastomas are the most common adipocytic tumors in children, but if a tumor is located in the deep tissue or imaging findings are not typical, the possibility of ALT should be considered and immunohistochemistry for MDM2 and CDK4 should be added. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Biolayer Interferometry Assay for Cyclin-Dependent Kinase-Cyclin Association Reveals Diverse Effects of Cdk2 Inhibitors on Cyclin Binding Kinetics
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Tambo, Carrie S, Tripathi, Sarvind, Perera, B Gayani K, Maly, Dustin J, Bridges, Alexander J, Kiss, Gert, and Rubin, Seth M
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Biochemistry and Cell Biology ,Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Biological Sciences ,Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Cyclin-Dependent Kinases ,Protein Serine-Threonine Kinases ,CDC2-CDC28 Kinases ,Cyclin-Dependent Kinase 2 ,Cyclins ,Phosphorylation ,Cyclin-Dependent Kinase 4 ,Organic Chemistry ,Biological sciences ,Chemical sciences - Abstract
Cyclin-dependent kinases (CDKs) are key mediators of cell proliferation and have been a subject of oncology drug discovery efforts for over two decades. Several CDK and activator cyclin family members have been implicated in regulating the cell division cycle. While it is thought that there are canonical CDK-cyclin pairing preferences, the extent of selectivity is unclear, and increasing evidence suggests that the cell-cycle CDKs can be activated by a pool of available cyclins. The molecular details of CDK-cyclin specificity are not completely understood despite their importance for understanding cancer cell cycles and for pharmacological inhibition of cancer proliferation. We report here a biolayer interferometry assay that allows for facile quantification of CDK binding interactions with their cyclin activators. We applied this assay to measure the impact of Cdk2 inhibitors on Cyclin A (CycA) association and dissociation kinetics. We found that Type I inhibitors increase the affinity between Cdk2 and CycA by virtue of a slowed cyclin dissociation rate. In contrast, Type II inhibitors and other small-molecule Cdk2 binders have distinct effects on the CycA association and dissociation processes to decrease affinity. We propose that the differential impact of small molecules on the cyclin binding kinetics arises from the plasticity of the Cdk2 active site as the kinase transitions between active, intermediate, and inactive states.
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- 2023
6. An Activity-Based Oxaziridine Platform for Identifying and Developing Covalent Ligands for Functional Allosteric Methionine Sites: Redox-Dependent Inhibition of Cyclin-Dependent Kinase 4
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Gonzalez-Valero, Angel, Reeves, Audrey G, Page, Annika CS, Moon, Patrick J, Miller, Edward, Coulonval, Katia, Crossley, Steven WM, Xie, Xiao, He, Dan, Musacchio, Patricia Z, Christian, Alec H, McKenna, Jeffrey M, Lewis, Richard A, Fang, Eric, Dovala, Dustin, Lu, Yipin, McGregor, Lynn M, Schirle, Markus, Tallarico, John A, Roger, Pierre P, Toste, F Dean, and Chang, Christopher J
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Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Breast Cancer ,Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Humans ,Female ,Cyclin-Dependent Kinase 4 ,Methionine ,Ligands ,Phosphorylation ,Oxidation-Reduction ,Racemethionine ,Breast Neoplasms ,General Chemistry ,Chemical sciences ,Engineering - Abstract
Activity-based protein profiling (ABPP) is a versatile strategy for identifying and characterizing functional protein sites and compounds for therapeutic development. However, the vast majority of ABPP methods for covalent drug discovery target highly nucleophilic amino acids such as cysteine or lysine. Here, we report a methionine-directed ABPP platform using Redox-Activated Chemical Tagging (ReACT), which leverages a biomimetic oxidative ligation strategy for selective methionine modification. Application of ReACT to oncoprotein cyclin-dependent kinase 4 (CDK4) as a representative high-value drug target identified three new ligandable methionine sites. We then synthesized a methionine-targeting covalent ligand library bearing a diverse array of heterocyclic, heteroatom, and stereochemically rich substituents. ABPP screening of this focused library identified 1oxF11 as a covalent modifier of CDK4 at an allosteric M169 site. This compound inhibited kinase activity in a dose-dependent manner on purified protein and in breast cancer cells. Further investigation of 1oxF11 found prominent cation-π and H-bonding interactions stabilizing the binding of this fragment at the M169 site. Quantitative mass-spectrometry studies validated 1oxF11 ligation of CDK4 in breast cancer cell lysates. Further biochemical analyses revealed cross-talk between M169 oxidation and T172 phosphorylation, where M169 oxidation prevented phosphorylation of the activating T172 site on CDK4 and blocked cell cycle progression. By identifying a new mechanism for allosteric methionine redox regulation on CDK4 and developing a unique modality for its therapeutic intervention, this work showcases a generalizable platform that provides a starting point for engaging in broader chemoproteomics and protein ligand discovery efforts to find and target previously undruggable methionine sites.
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- 2022
7. MDM2 Gene Amplification and Expression of MDM2 and CDK4 are Rare in Ossifying Fibroma of Craniofacial Bones
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Bahceci, Dorukhan H, Jordan, Richard CK, and Horvai, Andrew E
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Biomedical and Clinical Sciences ,Clinical Sciences ,Dentistry ,Rare Diseases ,Dental/Oral and Craniofacial Disease ,Pediatric ,Cancer ,Genetics ,Humans ,In Situ Hybridization ,Fluorescence ,Gene Amplification ,Proto-Oncogene Proteins c-mdm2 ,Cyclin-Dependent Kinase 4 ,Ossifying fibroma ,MDM2 amplification ,Immunohistochemistry ,Fluorescence in situ hybridization ,Osteosarcoma ,Clinical sciences - Abstract
Ossifying fibroma of the craniofacial bones is a fibro-osseous lesion characterized by varied patterns of bone formation in a fibroblastic stroma. Ossifying fibroma is a putatively benign lesion with no reports of malignant transformation or metastasis. Differentiation from other fibro-osseous lesions can be challenging necessitating synthesis of clinical, radiological and pathological findings. The molecular pathogenesis of ossifying fibroma is poorly understood but recent studies have reported MDM2 gene amplification and chromosomal copy number changes in a subset of ossifying fibromas. MDM2 amplification in ossifying fibroma, if true, presents a diagnostic problem because this genetic event, at least among craniofacial fibro-osseous lesions, was previously considered specific for low-grade osteosarcoma. In the present study, we investigated the utility of MDM2 and CDK4 immunohistochemistry, and fluorescence in situ hybridization for MDM2 gene amplification, in the diagnosis of 44 craniofacial bone ossifying fibromas. Focal MDM2 and CDK4 nuclear immunoreactivity was found in 11 and 1 ossifying fibromas, respectively, but none demonstrated MDM2 amplification by fluorescence in situ hybridization. A single tumor displayed MDM2 amplification without nuclear immunoreactivity to either MDM2 or CDK4. Our data suggest that while focal MDM2 and CDK4 nuclear expression may be detected in a minority of ossifying fibromas, this expression does not correlate with MDM2 amplification. In addition, MDM2 amplification is extremely rare in ossifying fibroma so the detection of this genetic abnormality should continue to raise concern for osteosarcoma.
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- 2022
8. 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
9. 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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10. 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
11. Extracellular vesicles from neurons promote neural induction of stem cells through cyclin D1
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Song, Lu, Tian, Xinran, and Schekman, Randy
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Stem Cell Research - Embryonic - Non-Human ,Stem Cell Research ,Neurosciences ,1.1 Normal biological development and functioning ,Underpinning research ,Neurological ,Animals ,Cell Communication ,Cell Differentiation ,Cell Line ,Cell Line ,Tumor ,Cyclin D1 ,Cyclin-Dependent Kinase 4 ,DNA-Binding Proteins ,Endosomal Sorting Complexes Required for Transport ,Extracellular Vesicles ,Gene Expression Regulation ,HSC70 Heat-Shock Proteins ,Membrane Proteins ,Mice ,Mouse Embryonic Stem Cells ,Nestin ,Neurogenesis ,Neurons ,PAX6 Transcription Factor ,PC12 Cells ,Rats ,Signal Transduction ,Transcription Factors ,Tretinoin ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Extracellular vesicles (EVs) are thought to mediate the transport of proteins and RNAs involved in intercellular communication. Here, we show dynamic changes in the buoyant density and abundance of EVs that are secreted by PC12 cells stimulated with nerve growth factor (NGF), N2A cells treated with retinoic acid to induce neural differentiation, and mouse embryonic stem cells (mESCs) differentiated into neuronal cells. EVs secreted from in vitro differentiated cells promote neural induction of mESCs. Cyclin D1 enriched within the EVs derived from differentiated neuronal cells contributes to this induction. EVs purified from cells overexpressing cyclin D1 are more potent in neural induction of mESC cells. Depletion of cyclin D1 from the EVs reduced the neural induction effect. Our results suggest that EVs regulate neural development through sorting of cyclin D1.
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- 2021
12. 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
13. 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
14. Prognostic value of [18F]-FDG PET/CT in patients with metastatic breast cancer treated with cyclin-dependent inhibitors.
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Annovazzi, Alessio, Rea, Sandra, Maccora, Daria, Pizzuti, Laura, Ferretti, Gianluigi, Vici, Patrizia, Cappuzzo, Federico, and Sciuto, Rosa
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CYCLIN-dependent kinases ,PROGNOSIS ,METASTATIC breast cancer ,ERIBULIN ,CYCLIN-dependent kinase inhibitors ,POSITRON emission tomography computed tomography ,COMPUTED tomography ,HORMONE therapy - Abstract
Objective: The addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to endocrine therapy impressively improved the outcome of patients with hormone receptor-positive metastatic breast cancer. Despite their great efficacy, not all patients respond to treatment and many of them develop acquired resistance. The aim of this retrospective study was to assess the role of [18F]-FDG PET/CT in predicting PFS and OS in breast cancer patients treated with CDK4/6i. Methods: 114 patients who performed an [18F]-FDG PET/CT scan before (PET1) and 2-6 months (PET2) after starting treatment were retrospectively enrolled. Metabolic response was evaluated by EORTC, PERCIST and Deauville Score and correlated to PFS and OS. Results: In patients who did not progress at PET2 (n = 90), PFS rates were not significantly different between classes of response by EORTC and PERCIST. Conversely, patients showing a Deauville score =3 had a longer PFS (median PFS 42 vs 21.0 months; p = 0.008). A higher total metabolic tumor volume at PET1 (TMTV1) was also associated with a shorter PFS (median 18 vs 42 months; p = 0.0026). TMTV1 and Deauville score were the only independent prognostic factors for PFS at multivariate analysis and their combination stratified the population in four definite classes of relapse risk. Conversely, the above parameters did not affect OS which was only influenced by a progressive metabolic disease at PET2 (3-years survival rate 29.8 vs 84.9%; p<0.0001). Conclusion: TMTV and metabolic response by Deauville score were significant prognostic factors for PFS in patients with breast cancer treated with CDK4/6i. Their determination could help physicians to select patients who may need a closer follow up. [ABSTRACT FROM AUTHOR]
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- 2023
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15. 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
16. 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
17. 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
18. 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
19. CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity
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Watt, April C, Cejas, Paloma, DeCristo, Molly J, Metzger-Filho, Otto, Lam, Enid YN, Qiu, Xintao, BrinJones, Haley, Kesten, Nikolas, Coulson, Rhiannon, Font-Tello, Alba, Lim, Klothilda, Vadhi, Raga, Daniels, Veerle W, Montero, Joan, Taing, Len, Meyer, Clifford A, Gilan, Omer, Bell, Charles C, Korthauer, Keegan D, Giambartolomei, Claudia, Pasaniuc, Bogdan, Seo, Ji-Heui, Freedman, Matthew L, Ma, Cynthia, Ellis, Matthew J, Krop, Ian, Winer, Eric, Letai, Anthony, Brown, Myles, Dawson, Mark A, Long, Henry W, Zhao, Jean J, and Goel, Shom
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Genetics ,Breast Cancer ,Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Animals ,Breast Neoplasms ,Cell Cycle Checkpoints ,Cyclin-Dependent Kinase 4 ,Female ,Genes ,cdc ,Humans ,Mice ,Transcription Factor AP-1 - Abstract
Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) were designed to induce cancer cell cycle arrest. Recent studies have suggested that these agents also exert other effects, influencing cancer cell immunogenicity, apoptotic responses, and differentiation. Using cell-based and mouse models of breast cancer together with clinical specimens, we show that CDK4/6 inhibitors induce remodeling of cancer cell chromatin characterized by widespread enhancer activation, and that this explains many of these effects. The newly activated enhancers include classical super-enhancers that drive luminal differentiation and apoptotic evasion, as well as a set of enhancers overlying endogenous retroviral elements that is enriched for proximity to interferon-driven genes. Mechanistically, CDK4/6 inhibition increases the level of several Activator Protein-1 (AP-1) transcription factor proteins, which are in turn implicated in the activity of many of the new enhancers. Our findings offer insights into CDK4/6 pathway biology and should inform the future development of CDK4/6 inhibitors.
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- 2021
20. 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
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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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
22. 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
23. Prognostic value of [18F]-FDG PET/CT in patients with meta-static breast cancer treated with cyclin-dependent inhibitors
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Alessio Annovazzi, Sandra Rea, Daria Maccora, Laura Pizzuti, Gianluigi Ferretti, Patrizia Vici, Federico Cappuzzo, and Rosa Sciuto
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PET-CT scan ,fluorodeoxyglucose F18 ,breast cancer ,cyclin-dependent kinase 4 ,progression-free and overall survival ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
ObjectiveThe addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to endocrine therapy impressively improved the outcome of patients with hormone receptor-positive metastatic breast cancer. Despite their great efficacy, not all patients respond to treatment and many of them develop acquired resistance. The aim of this retrospective study was to assess the role of [18F]-FDG PET/CT in predicting PFS and OS in breast cancer patients treated with CDK4/6i.Methods114 patients who performed an [18F]-FDG PET/CT scan before (PET1) and 2-6 months (PET2) after starting treatment were retrospectively enrolled. Metabolic response was evaluated by EORTC, PERCIST and Deauville Score and correlated to PFS and OS.ResultsIn patients who did not progress at PET2 (n = 90), PFS rates were not significantly different between classes of response by EORTC and PERCIST. Conversely, patients showing a Deauville score ≤3 had a longer PFS (median PFS 42 vs 21.0 months; p = 0.008). A higher total metabolic tumor volume at PET1 (TMTV1) was also associated with a shorter PFS (median 18 vs 42 months; p = 0.0026). TMTV1 and Deauville score were the only independent prognostic factors for PFS at multivariate analysis and their combination stratified the population in four definite classes of relapse risk. Conversely, the above parameters did not affect OS which was only influenced by a progressive metabolic disease at PET2 (3-years survival rate 29.8 vs 84.9%; p
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- 2023
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24. 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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25. 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
26. 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
27. Germline mutations predisposing to melanoma
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Toussi, Atrin, Mans, Nicole, Welborn, Jeanna, and Kiuru, Maija
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Genetics ,Cancer ,Rare Diseases ,Genetic Testing ,Aetiology ,2.1 Biological and endogenous factors ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase Inhibitor p16 ,Genes ,p16 ,Genetic Predisposition to Disease ,Germ-Line Mutation ,Humans ,Melanoma ,Microphthalmia-Associated Transcription Factor ,Middle Aged ,Nevus ,Pigmented ,Phenotype ,Receptor ,Melanocortin ,Type 1 ,Shelterin Complex ,Telomerase ,Telomere-Binding Proteins ,Tumor Suppressor Proteins ,Ubiquitin Thiolesterase ,Young Adult ,CDKN2A ,germline mutation ,hereditary ,melanocytic nevus ,melanoma ,Clinical Sciences ,Dermatology & Venereal Diseases ,Clinical sciences - Abstract
Nearly 15% of melanomas occur in patients with a family history and a subset of these patients have a germline mutation in a melanoma predisposing gene. CDKN2A mutations are responsible for the majority of hereditary melanoma, but many other susceptibility genes have been discovered in recent years, including CDK4, TERT, ACD, TERF2IP, POT1, MITF, MC1R, and BAP1. Additionally, melanoma risk is increased in mixed cancer syndromes caused by mutations in PTEN, BRCA2, BRCA1, RB1, and TP53. While early onset, multiple tumors, and family cancer history remain the most valuable clinical clues for hereditary melanoma, characteristic epithelioid cytology of melanocytic tumors may suggest an underlying BAP1 mutation. Herein, we review the clinical and histopathologic characteristics of melanocytic tumors associated with these germline mutations and discuss the role of genetic counseling.
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- 2020
28. 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
29. p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition
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Guiley, Keelan Z, Stevenson, Jack W, Lou, Kevin, Barkovich, Krister J, Kumarasamy, Vishnu, Wijeratne, Tilini U, Bunch, Katharine L, Tripathi, Sarvind, Knudsen, Erik S, Witkiewicz, Agnieszka K, Shokat, Kevan M, and Rubin, Seth M
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Biochemistry and Cell Biology ,Chemical Sciences ,Biological Sciences ,Cancer ,Rare Diseases ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Allosteric Regulation ,Antineoplastic Agents ,Biocatalysis ,Cell Line ,Tumor ,Crystallography ,X-Ray ,Cyclin D1 ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase Inhibitor p27 ,Enzyme Activation ,Humans ,Phosphorylation ,Piperazines ,Protein Conformation ,Protein Kinase Inhibitors ,Pyridines ,Retinoblastoma Protein ,General Science & Technology - Abstract
The p27 protein is a canonical negative regulator of cell proliferation and acts primarily by inhibiting cyclin-dependent kinases (CDKs). Under some circumstances, p27 is associated with active CDK4, but no mechanism for activation has been described. We found that p27, when phosphorylated by tyrosine kinases, allosterically activated CDK4 in complex with cyclin D1 (CDK4-CycD1). Structural and biochemical data revealed that binding of phosphorylated p27 (phosp27) to CDK4 altered the kinase adenosine triphosphate site to promote phosphorylation of the retinoblastoma tumor suppressor protein (Rb) and other substrates. Surprisingly, purified and endogenous phosp27-CDK4-CycD1 complexes were insensitive to the CDK4-targeting drug palbociclib. Palbociclib instead primarily targeted monomeric CDK4 and CDK6 (CDK4/6) in breast tumor cells. Our data characterize phosp27-CDK4-CycD1 as an active Rb kinase that is refractory to clinically relevant CDK4/6 inhibitors.
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- 2019
30. Cervical Liposarcoma Revisited: A Case Report and Scoping Literature Review
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Takahiro Suzuki, Naoya Noguchi, Shion Shirane, Nanako Ansai, Teruyuki Sato, Kazue Ise, Keigo Murakami, Kazuhiro Murakami, Yasuhiro Nakamura, and Nobuo Ohta
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cervical liposarcoma ,murine double minute 2 ,cyclin-dependent kinase 4 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The commonest sites for liposarcoma are the retroperitoneum and lower extremities. Liposarcoma of the head and neck region is a rare and potentially life-threatening malignancy. Tumors originating in the right cervical space cause special diagnostic and therapeutic difficulties. In the present report, we describe a case of differentiated liposarcoma of the right cervical region. The tumor continued to grow slowly over 3 years before a definitive diagnosis was established. Extended extirpation of the tumor was performed and proved efficacious in that no recurrence has been observed for 4 years. Recommendations for earlier and accurate diagnosis and treatment of this rare neoplasm are discussed.
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- 2022
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31. Immortalized Canine Adipose-Derived Mesenchymal Stem Cells as a Novel Candidate Cell Source for Mesenchymal Stem Cell Therapy.
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Yasumura, Yuyo, Teshima, Takahiro, Nagashima, Tomokazu, Takano, Takashi, Michishita, Masaki, Taira, Yoshiaki, Suzuki, Ryohei, and Matsumoto, Hirotaka
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STEM cell treatment , *TELOMERASE reverse transcriptase , *MESENCHYMAL stem cells , *CELL cycle , *CELLULAR aging , *ANIMAL diseases - Abstract
Mesenchymal stem cells are expected to be a cell source for stem cell therapy of various diseases in veterinary medicine. However, donor-dependent cell heterogenicity has been a cause of inconsistent therapeutic efficiency. Therefore, we established immortalized cells from canine adipose tissue-derived mesenchymal stem cells (ADSCs) to minimize cellular heterogeneity by reducing the number of donors, evaluated their properties, and compared them to the primary cells with RNA-sequencing. Immortalized canine ADSCs were established by transduction with combinations of the R24C mutation of human cyclin-dependent kinase 4 (CDKR24C), canine cyclin D1, and canine TERT. The ADSCs transduced with CDK4R24C, cyclin D1, and TERT (ADSC-K4DT) or with CDK4R24C and cyclin D1 (ADSC-K4D) showed a dramatic increase in proliferation (population doubling level > 100) without cellular senescence compared to the primary ADSCs. The cell surface markers, except for CD90 of the ADSC-K4DT and ADSC-K4D cells, were similar to those of the primary ADSCs. The ADSC-K4DT and ADSC-K4D cells maintained their trilineage differentiation capacity and chromosome condition, and did not have a tumorigenic development. The ability to inhibit lymphocyte proliferation by the ADSC-K4D cells was enhanced compared with the primary ADSCs and ADSC-K4DT cells. The pathway analysis based on RNA-sequencing revealed changes in the pathways mainly related to the cell cycle and telomerase. The ADSC-K4DT and ADSC-K4D cells had decreased CD90 expression, but there were no obvious defects associated with the decreased CD90 expression in this study. Our results suggest that ADSC-K4DT and ADSC-K4D cells are a potential novel cell source for mesenchymal stem cell therapy. [ABSTRACT FROM AUTHOR]
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- 2023
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32. 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
- Subjects
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]
- Published
- 2023
- Full Text
- View/download PDF
33. Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets.
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Newell, Felicity, Kong, Yan, Wilmott, James S, Johansson, Peter A, Ferguson, Peter M, Cui, Chuanliang, Li, Zhongwu, Kazakoff, Stephen H, Burke, Hazel, Dodds, Tristan J, Patch, Ann-Marie, Nones, Katia, Tembe, Varsha, Shang, Ping, van der Weyden, Louise, Wong, Kim, Holmes, Oliver, Lo, Serigne, Leonard, Conrad, Wood, Scott, Xu, Qinying, Rawson, Robert V, Mukhopadhyay, Pamela, Dummer, Reinhard, Levesque, Mitchell P, Jönsson, Göran, Wang, Xuan, Yeh, Iwei, Wu, Hong, Joseph, Nancy, Bastian, Boris C, Long, Georgina V, Spillane, Andrew J, Shannon, Kerwin F, Thompson, John F, Saw, Robyn PM, Adams, David J, Si, Lu, Pearson, John V, Hayward, Nicholas K, Waddell, Nicola, Mann, Graham J, Guo, Jun, and Scolyer, Richard A
- Subjects
Melanocytes ,Humans ,Melanoma ,Telomerase ,Signal Transduction ,Point Mutation ,Female ,Male ,Cyclin-Dependent Kinase 4 ,Proto-Oncogene Proteins c-mdm2 ,DNA Copy Number Variations ,Biomarkers ,Tumor ,Whole Genome Sequencing ,Biomarkers ,Tumor - Abstract
Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.
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- 2019
34. 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
- Subjects
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
35. 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.
- Published
- 2019
36. 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
- Subjects
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.
- Published
- 2019
37. Synergistic Anticancer Effect of a Combination of Berbamine and Arcyriaflavin A against Glioblastoma Stem-like Cells.
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Han, Jang Mi and Jung, Hye Jin
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- *
CELL cycle proteins , *ANTINEOPLASTIC agents , *SMALL interfering RNA , *BRAIN tumors , *ALDEHYDE dehydrogenase , *CALMODULIN , *PROTEIN kinases , *P53 protein - Abstract
Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor. Relapse is frequent and rapid due to glioblastoma stem-like cells (GSCs) that induce tumor initiation, drug resistance, high cancer invasion, immune evasion, and recurrence. Therefore, suppression of GSCs is a powerful therapeutic approach for GBM treatment. Natural compounds berbamine and arcyriaflavin A (ArcA) are known to possess anticancer activity by targeting calcium/calmodulin-dependent protein kinase II gamma (CaMKIIγ) and cyclin-dependent kinase 4 (CDK4), respectively. In this study, we evaluated the effects of concurrent treatment with both compounds on GSCs. Combined treatment with berbamine and ArcA synergistically inhibited cell viability and tumorsphere formation in U87MG- and C6-drived GSCs. Furthermore, simultaneous administration of both compounds potently inhibited tumor growth in a U87MG GSC-grafted chick embryo chorioallantoic membrane (CAM) model. Notably, the synergistic anticancer effect of berbamine and ArcA on GSC growth is associated with the promotion of reactive oxygen species (ROS)- and calcium-dependent apoptosis via strong activation of the p53-mediated caspase cascade. Moreover, co-treatment with both compounds significantly reduced the expression levels of key GSC markers, including CD133, integrin α6, aldehyde dehydrogenase 1A1 (ALDH1A1), Nanog, Sox2, and Oct4. The combined effect of berbamine and ArcA on GSC growth also resulted in downregulation of cell cycle regulatory proteins, such as cyclins and CDKs, by potent inactivation of the CaMKIIγ-mediated STAT3/AKT/ERK1/2 signaling pathway. In addition, a genetic knockdown study using small interfering RNAs (siRNAs) targeting either CaMKIIγ or CDK4 demonstrated that the synergistic anticancer effect of the two compounds on GSCs resulted from dual inhibition of CaMKIIγ and CDK4. Collectively, our findings suggest that a novel combination therapy involving berbamine and ArcA could effectively eradicate GSCs. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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38. 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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39. Hernandezine acts as a CDK4 suppressor inhibiting tumor growth by the CDK4/PKM2/NRF2 axis in colon cancer.
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Lv, Jun-lin, Ren, Yu-shan, Tan, Yu-jun, Chu, Ting, Cao, Xin-yue, Liu, Huai-yuan, Ma, Ru, Zhang, Han, Zheng, Qiu-sheng, Dong, Gui-cheng, and Li, Jie
- Abstract
• PKM2 and NRF2 are endogenous substrates of CDK4 in CC tissues. • Inactivated CDK4 inhibits PKM2 enzymatic and NRF2 transcriptional activity in CC cells. • HER inhibits CDK4 by binding two amino acid site (140 Asp and 145 Asn) of CDK4. • HER exerts triple anti-tumor effects by inhibiting CDK4-PKM2-NRF2 axis in CC cells. The cyclin-dependent kinase 4 (CDK4) interacts with its canonical and non-canonical substrates modulating the cell cycle in tumor cells. However, the potential substrates and the beyond-cell-cycle-regulated functions of CDK4 in colon cancer (CC) are still unknown. Hernandezine (HER) is previously verified to induce G0/G1 phase arrest and autophagic cell death in human cancer cells, which implies that HER might target G0/G1 phase-related proteins, including CDK4. The present study tried to investigate the glycolytic metabolism and oxidative stress functions of CDK4 in colon cancer. Furthermore, the inhibitory effects and potential binding sites of HER on CDK4, as well as its anti-tumor activity were investigated in CC cells. The mass spectrometry assay was performed to identify potential endogenous substrates of CDK4 and the correlation between glycolytic metabolic rate and CDK4 level in COAD patient tissues. Meanwhile, after inhibiting the activity or the expression of CDK4, the binding capacity of CDK4 to PKM2 and NRF2 and the latter two protein distributions in cytoplasm and nucleus were detected in CC cells. In vitro , the regulatory effects of the CDK4-PKM2-NRF2 axis on glycolysis and oxidative stress were performed by ECAR, OCR, and ROS assay. The inhibitory effect of HER on CDK4 activity was explored in CC cells and the potential binding sites were predicted and testified in vitro. Furthermore, tumor growth inhibition of HER by suppressing the CDK4-PKM2-NRF2 axis was also investigated in vitro and in vivo. PKM2 and NRF2 were identified as endogenous substrates of CDK4 and, high-expressed CDK4 was associated with low-level glycolysis in COAD. In vitro , inactivated CDK4 facilitated CDK4-PKM2-NRF2 complex formation which resulted in 1) inhibited PKM2 activity and retarded the glycolytic rate; 2) cytoplasm-detained NRF2 failed to transcript anti-oxidative gene expressions and induced oxidant stress. Additionally, as a CDK4 inhibitor, HER developed triple anti-tumor effects including induced G0/G1 phase arrest, suppressed glycolysis, and disrupted the anti-oxidative capacity of CC cells. : The results first time revealed that CDK4 modulated glycolytic and anti-oxidative capacity of CC cells via bound to its endogenous substrates, PKM2 and NRF2. Additionally, 140 Asp 145 Asn amino acid sites of CDK4 were potential targets of HER. HER exerts anti-tumor activity by inhibited the activity of CDK4, promoted the CDK4-PKM2-NRF2 complex formation in the CC cells. [Display omitted] [ABSTRACT FROM AUTHOR]
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- 2024
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40. Inhibition of cyclin-dependent kinase 4 as a potential therapeutic strategy for treatment of synovial sarcoma.
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Li, Xiaoyang, Seebacher, Nicole A, Garbutt, Cassandra, Ma, Hangzhan, Gao, Peng, Xiao, Tao, Hornicek, Francis J, and Duan, Zhenfeng
- Subjects
Cell Line ,Tumor ,Humans ,Sarcoma ,Synovial ,Piperazines ,Pyridines ,Neoplasm Proteins ,Protein Kinase Inhibitors ,Gene Expression Regulation ,Enzymologic ,Gene Expression Regulation ,Neoplastic ,Cyclin-Dependent Kinase 4 ,Clinical Research ,Rare Diseases ,Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Biochemistry and Cell Biology ,Oncology and Carcinogenesis - Abstract
Synovial sarcoma is a highly aggressive but rare form of soft tissue malignancy that primarily affects the extremities of the arms or legs, for which current chemotherapeutic agents have not been proven to be very effective. The cyclin-dependent kinase 4/6-retinoblastoma protein (CDK4/6-Rb) pathway of cell cycle control is known to be aberrant in a large proportion of cancers. Recently, CDK4 inhibitors have successfully been used pre-clinically for the treatment of many human cancers, and in 2015, following the success of clinical trials, the FDA approved the first selective CDK4/6 inhibitor, palbociclib, for the treatment of endocrine therapy resistant breast cancers. However, the expression and therapeutic potential of targeting CDK4 in synovial sarcoma remains unclear. In the present study, we report that CDK4 is highly expressed in human synovial sarcoma, and high CDK4 expressions are associated with poor prognosis in sarcomas patients and the clinical stage and the TNM grade in synovial sarcoma patients. Knockdown of CDK4 with specific small interference RNAs inhibits cell proliferation and enhances apoptotic effects in synovial sarcoma cells. CDK4 inhibitor palbociclib suppresses synovial sarcoma cell proliferation and growth in a dose and time-dependent manner. Palbociclib also inhibits the CDK4/6-Rb signaling pathway and promotes cell apoptosis without changing CDK4/6 protein levels, suggesting that palbociclib only represses the hyper-activation, not the expression of CDK4/6. Flow cytometry analysis reveals that palbociclib induces G1 cell-cycle arrest and apoptotic effects by targeting the CDK4/6-Rb pathway in synovial sarcoma cells. Furthermore, wound healing assays demonstrate that inhibition of the CDK4/6-Rb pathway by palbociclib significantly decreases synovial sarcoma cell migration in vitro. Our study highlights the importance of the CDK4/6-Rb pathway in human synovial sarcoma pathogenesis, and the role of the current selective CDK4/6 inhibitor, palbociclib, as a potential promising targeted therapeutic agent in the treatment of human synovial sarcoma.
- Published
- 2018
41. Regulation of Cell Cycle to Stimulate Adult Cardiomyocyte Proliferation and Cardiac Regeneration
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Mohamed, Tamer MA, Ang, Yen-Sin, Radzinsky, Ethan, Zhou, Ping, Huang, Yu, Elfenbein, Arye, Foley, Amy, Magnitsky, Sergey, and Srivastava, Deepak
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Heart Disease ,Regenerative Medicine ,Heart Disease - Coronary Heart Disease ,Cardiovascular ,2.1 Biological and endogenous factors ,Aetiology ,Underpinning research ,1.1 Normal biological development and functioning ,Generic health relevance ,Animals ,CDC2 Protein Kinase ,Cell Cycle Proteins ,Cell Proliferation ,Cyclin B1 ,Cyclin D1 ,Cyclin-Dependent Kinase 4 ,Cytokinesis ,Heart ,Humans ,Induced Pluripotent Stem Cells ,Mice ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Myocardial Infarction ,Myocytes ,Cardiac ,Myosin Heavy Chains ,Nuclear Proteins ,Protein-Tyrosine Kinases ,Rats ,Regeneration ,Transforming Growth Factor beta ,CDK ,cardiomyocyte ,cell cycle ,cell division ,cyclin ,cytokinesis ,heart ,heart failure ,proliferation ,regeneration ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Human diseases are often caused by loss of somatic cells that are incapable of re-entering the cell cycle for regenerative repair. Here, we report a combination of cell-cycle regulators that induce stable cytokinesis in adult post-mitotic cells. We screened cell-cycle regulators expressed in proliferating fetal cardiomyocytes and found that overexpression of cyclin-dependent kinase 1 (CDK1), CDK4, cyclin B1, and cyclin D1 efficiently induced cell division in post-mitotic mouse, rat, and human cardiomyocytes. Overexpression of the cell-cycle regulators was self-limiting through proteasome-mediated degradation of the protein products. In vivo lineage tracing revealed that 15%-20% of adult cardiomyocytes expressing the four factors underwent stable cell division, with significant improvement in cardiac function after acute or subacute myocardial infarction. Chemical inhibition of Tgf-β and Wee1 made CDK1 and cyclin B dispensable. These findings reveal a discrete combination of genes that can efficiently unlock the proliferative potential in cells that have terminally exited the cell cycle.
- Published
- 2018
42. Cervical Liposarcoma Revisited: A Case Report and Scoping Literature Review.
- Author
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Suzuki, Takahiro, Noguchi, Naoya, Shirane, Shion, Ansai, Nanako, Sato, Teruyuki, Ise, Kazue, Murakami, Keigo, Murakami, Kazuhiro, Nakamura, Yasuhiro, and Ohta, Nobuo
- Subjects
- *
LIPOSARCOMA , *LITERATURE reviews , *RETROPERITONEUM , *EARLY diagnosis - Abstract
The commonest sites for liposarcoma are the retroperitoneum and lower extremities. Liposarcoma of the head and neck region is a rare and potentially life-threatening malignancy. Tumors originating in the right cervical space cause special diagnostic and therapeutic difficulties. In the present report, we describe a case of differentiated liposarcoma of the right cervical region. The tumor continued to grow slowly over 3 years before a definitive diagnosis was established. Extended extirpation of the tumor was performed and proved efficacious in that no recurrence has been observed for 4 years. Recommendations for earlier and accurate diagnosis and treatment of this rare neoplasm are discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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43. Case report: Atypical lipomatous tumor of the thigh in a four-year-old girl.
- Author
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Ogawa I, Hakozaki M, Kaneuchi Y, Suzuki T, Nikaido T, Yamada S, Utsumi A, Hasegawa O, Sano H, and Matsumoto Y
- Abstract
Atypical lipomatous tumors (ALTs) are locally aggressive adipocytic malignancies that frequently occur in middle-aged adults. We report the rare case of an ALT of the thigh that occurred in a 4-year-old girl. Since the tumor was initially diagnosed as a lipoblastoma by incisional biopsy, marginal resection was performed. Histopathological findings of the surgical specimen revealed the proliferation of mature and variously sized adipocytes, as well as ectopic ossification; these features differ from the typical findings of lipoblastoma. Immunohistochemical findings showed nuclear positivity for a murine double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) and negativity for pleomorphic adenoma gene 1 (PLAG1). Fluorescence in situ hybridization showed abnormal amplification of the MDM2 gene. The patient was thus finally diagnosed as having an ALT. No signs of local recurrence or metastasis were noted 1 year postoperatively. This case is instructive in the differential diagnosis of primary adipocytic tumors. Lipoblastomas are the most common adipocytic tumors in children, but if a tumor is located in the deep tissue or imaging findings are not typical, the possibility of ALT should be considered and immunohistochemistry for MDM2 and CDK4 should be added., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ogawa, Hakozaki, Kaneuchi, Suzuki, Nikaido, Yamada, Utsumi, Hasegawa, Sano and Matsumoto.)
- Published
- 2024
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44. 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.
- Author
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Hyehyun Jeong, Jae Ho Jeong, Jeong Eun Kim, Jin-Hee Ahn, Kyung Hae Jung, and Sung-Bae Kim
- Subjects
- *
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]
- Published
- 2022
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45. Studies from University Libre of Bruxelles (U.L.B.) Have Provided New Data on Breast Cancer (Effect of Cyclin-Dependent Kinase 4/6 Inhibitors on Circulating Cells in Patients with Metastatic Breast Cancer).
- Abstract
A recent study conducted by the University Libre of Bruxelles (U.L.B.) has examined the effects of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) on circulating cells in patients with metastatic breast cancer. The combination of CDK4/6i with endocrine therapy is the standard treatment for estrogen receptor-positive, HER2-negative advanced/metastatic breast cancer. The study found that CDK4/6i+ET resulted in significant changes in hematological parameters and immune cell subsets. The research highlights the importance of considering immune dynamics in the management of this type of breast cancer. [Extracted from the article]
- Published
- 2024
46. New Kinase Inhibitors Study Results Reported from Manipal College of Pharmaceutical Sciences (Strategy To Improve the Oral Pharmacokinetics of Cyclin-dependent Kinase 4/6 Inhibitors: Enhancing Permeability and Cyp450 Inhibition By a Natural...).
- Abstract
A study conducted by researchers at Manipal College of Pharmaceutical Sciences in Karnataka, India, has found that the bioavailability of cyclin-dependent kinase 4/6 inhibitors, palbociclib and ribociclib, can be improved by the concurrent administration of naringin, a natural bioenhancer. The researchers discovered that naringin binds optimally to CYP3A4 and P-glycoprotein, reducing the metabolism of palbociclib and ribociclib and increasing their oral exposure. This finding suggests that the use of naringin alongside these kinase inhibitors could be an innovative strategy for enhancing their bioavailability. The study was supported by Manipal Academy of Higher Education, Manipal center for molecular simulation, and the Indian Council of Medical Research. [Extracted from the article]
- Published
- 2024
47. New Findings in Lung Cancer Described from Rutgers University - The State University of New Jersey (A Review of Trilaciclib, a First-in-class Cyclin-dependent Kinase 4/6 Inhibitor, for the Management of Metastatic Small-cell Lung Cancer).
- Abstract
A report from Rutgers University - The State University of New Jersey discusses the use of a first-in-class cyclin-dependent kinase 4/6 (CDK4/6) inhibitor called trilaciclib for the management of metastatic small-cell lung cancer (SCLC). CDKs play a crucial role in regulating cell cycle transitions, and inhibiting CDK4/6 has shown promise in treating breast cancer and other tumors. Trilaciclib is a third-generation inhibitor that offers improved selectivity and fewer side effects compared to previous inhibitors. It has been approved by the FDA to protect bone marrow suppression during chemotherapy for patients with metastatic-stage SCLC. [Extracted from the article]
- Published
- 2024
48. Study Data from Hacettepe University Update Understanding of Breast Cancer [The impact of human epidermal growth factor receptor-2 (low) status on the efficacy of first line cyclin-dependent kinase 4/6 inhibitors in advanced breast cancer].
- Abstract
A recent study conducted by Hacettepe University in Ankara, Turkey, examined the impact of human epidermal growth factor receptor 2 (HER2) status on the efficacy of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in advanced breast cancer. The study found that the HER2-low group, previously classified as HER2 negative, responded similarly to HER2-positive patients when treated with HER2-targeted therapies. The effectiveness of CDK4/6 inhibitors as a first-line treatment for hormone receptor-positive, HER2-negative advanced breast cancer in this newly defined histological subgroup remains a topic of debate. The study concluded that the progression-free survival achieved with CDK4/6 inhibitors is unaffected by HER2 status. [Extracted from the article]
- Published
- 2024
49. Phase II Clinical Study of Trastuzumab Emtansine (T-DM1) Combined With Cyclin-dependent Kinase 4/6 (CDK4/6) Inhibitor Ribociclib in the Treatment of Human Epidermal Growth Factor Receptor-2 (HER2)-Positive Advanced Breast Cancer.
- Abstract
This document provides information about a clinical trial, NCT06481956, that is currently underway in China. The trial is investigating the effectiveness and safety of combining Trastuzumab Emtansine (T-DM1) with the Cyclin-dependent Kinase 4/6 (CDK4/6) inhibitor Ribociclib in the treatment of advanced breast cancer that is positive for the Human Epidermal Growth Factor Receptor-2 (HER2). The trial aims to assess various outcomes, such as objective response rate, progression-free survival, overall survival, and adverse events. The study is a multicenter, single-arm Phase II trial and is currently enrolling participants. The trial is being led by Dr. Yabing Zheng from Zhejiang Cancer Hospital and aims to recruit a total of 40 patients. [Extracted from the article]
- Published
- 2024
50. Studies from Dana-Farber Cancer Institute Yield New Information about Breast Cancer (Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer-cyclin-dependent Kinase 4 and 6 Inhibitors: Asco Guideline Rapid Recommendation...).
- Abstract
A report from the Dana-Farber Cancer Institute in Boston, Massachusetts discusses research findings on breast cancer. The report highlights the ASCO Rapid Recommendation Updates, which provide revised guidelines based on new and practice-changing data. The goal of these updates is to inform healthcare practitioners and the public about the best available cancer care options. The research concludes with disclaimers and important information, and the full article can be accessed through the Journal of Clinical Oncology. [Extracted from the article]
- Published
- 2024
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