7,946 results on '"Cyclin-dependent kinase 4"'
Search Results
202. Synergistic cytotoxicity of the CDK4 inhibitor Fascaplysin in combination with EGFR inhibitor Afatinib against Non-small Cell Lung Cancer
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Barbara Rath, Adelina Plangger, Christoph Neumayer, Maximilian Hochmair, Gerhard Hamilton, Martin Funovics, and Robert Zeillinger
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Indoles ,Lung Neoplasms ,Afatinib ,medicine.medical_treatment ,Hyperphosphorylation ,Antineoplastic Agents ,Western blot ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Pharmacology (medical) ,Cytotoxicity ,Lung cancer ,Protein Kinase Inhibitors ,EGFR inhibitors ,Pharmacology ,Cisplatin ,Chemotherapy ,medicine.diagnostic_test ,Chemistry ,Cyclin-Dependent Kinase 4 ,medicine.disease ,respiratory tract diseases ,ErbB Receptors ,Oncology ,Mutation ,Cancer research ,medicine.drug - Abstract
SummaryIn the absence of suitable molecular markers, non-small cell lung cancer (NSCLC) patients have to be treated with chemotherapy with poor results at advanced stages. Therefore, the activity of the anticancer marine drug fascaplysin was tested against primary NSCLC cell lines established from pleural effusions. Cytotoxicity of the drug or combinations were determined using MTT assays and changes in intracellular phosphorylation by Western blot arrays. Fascaplysin revealed high cytotoxicity against NSCLC cells and exhibit an activity pattern different of the standard drug cisplatin. Furthermore, fascaplysin synergizes with the EGFR tyrosine kinase inhibitor (TKI) afatinib to yield a twofold increased antitumor effect. Interaction with the Chk1/2 inhibitor AZD7762 confirm the differential effects of fascplysin and cisplatin. Protein phosphorylation assays showed hypophosphorylation of Akt1/2/3 and ERK1/2 as well as hyperphosphorylation of stress response mediators of H1299 NSCLC cells. In conclusion, fascaplysin shows high cytotoxicity against pleural primary NSCLC lines that could be further boosted when combined with the EGFR TKI afatinib.
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- 2021
203. [Expert consensus on the management of adverse events of CDK4/6 inhibitors in breast cancer]
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R, Ge, B Y, Wang, and Z F, Jiang
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Consensus ,Humans ,Cyclin-Dependent Kinase 4 ,Aminopyridines ,Female ,Breast Neoplasms ,Antineoplastic Agents ,Protein Kinase Inhibitors - Abstract
Cyclin-dependent kinases 4/6 (CDK4/6) inhibitors are anti-tumor agents for the treatment of hormone receptor-positive breast cancer. Palbociclib, abemaciclib and dalpiciclib have been approved for the treatment of breast cancer in China. Common adverse effects of CDK4/6 inhibitors include bone marrow suppression, gastrointestinal toxicities, liver dysfunction, and skin or subcutaneous tissue adverse reactions (AEs). The Breast Cancer Expert Group of Chinese Society of Clinical Oncology (CSCO) summarized the incidence, clinical manifestations, and grading of the AEs. This expert consensus reports measures of AE management on the basis of experience of clinical practice and the latest advances worldwide, aiming to guide clinical practice by the way of managing AE and help to choose the best treatment regimen.细胞周期蛋白依赖性激酶4/6(CDK4/6)抑制剂是治疗激素受体阳性乳腺癌的抗肿瘤药物,其中,哌柏西利、阿贝西利和达尔西利已在中国获得批准用于乳腺癌的治疗。CDK4/6抑制剂常见的不良反应包括骨髓抑制、胃肠道不良反应、肝功能异常、皮肤及皮下组织不良反应等。中国临床肿瘤学会乳腺癌专家委员会共识专家组总结了CDK4/6抑制剂常见不良反应的发生率、临床表现和严重程度分级,结合临床经验并参考国内外研究进展,制定了不良事件的管理措施,形成乳腺癌CDK4/6抑制剂相关性不良反应管理共识,旨在从不良反应管理角度更好地指导临床实践,帮助选择CDK4/6抑制剂最佳治疗方案。.
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- 2022
204. Erratum
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Errata ,Receptors, Estrogen ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Humans ,Cyclin-Dependent Kinase 4 ,Breast Neoplasms ,Cyclin-Dependent Kinase 6 ,APOBEC Deaminases ,Immune Checkpoint Inhibitors ,United States - Abstract
APOBEC mutagenesis underlies somatic evolution and accounts for tumor heterogeneity in several cancers, including breast cancer (BC). In this study, we evaluated the characteristics of a real-world cohort for time-to-treatment discontinuation (TTD) and overall survival on CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) and immune checkpoint inhibitors.Comprehensive genomic profiling results from 29,833 BC samples were analyzed for tumor mutational burden and APOBEC signatures. For clinical outcomes, a deidentified nationwide (United States-based) BC Clinico-Genomic Database (CGDB) was evaluated with log-rank and Cox models. Patients with hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) BC who received first-line ET and CDK4/6i were included. Eligible patients from Mayo Clinic and Duke University were HR+ HER2- BC with sequencing data between September 2013 and July 2020.Of 29,833 samples sequenced, 7.9% were APOBEC+ with a high rate in invasive lobular carcinoma (16.7%) and in metastatic tumors (9.7%) relative to locally biopsied BC (4.3%;APOBEC+ HR+ HER2- patients had shorter TTD on first-line ET plus CDK4/6i relative to APOBEC- patients. Further research is needed to optimize the treatment of APOBEC+ HR+ HER2- BC and to investigate the efficacy of immunotherapeutic strategies in this population.
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- 2022
205. Phosphoproteomic analysis of neoadjuvant breast cancer suggests that increased sensitivity to paclitaxel is driven by CDK4 and filamin A
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S. Mouron, M. J. Bueno, A. Lluch, L. Manso, I. Calvo, J. Cortes, J. A. Garcia-Saenz, M. Gil-Gil, N. Martinez-Janez, J. V. Apala, E. Caleiras, Pilar Ximénez-Embún, J. Muñoz, L. Gonzalez-Cortijo, R. Murillo, R. Sánchez-Bayona, J. M. Cejalvo, G. Gómez-López, C. Fustero-Torre, S. Sabroso-Lasa, N. Malats, M. Martinez, A. Moreno, D. Megias, M. Malumbres, R. Colomer, M. Quintela-Fandino, Instituto de Salud Carlos III, European Commision, Comunidad de Madrid (España), Boehringer Ingelheim Fonds, CRIS contra el Cáncer, Institut Català de la Salut, [Mouron S, Bueno MJ] Breast Cancer Clinical Research Unit Centro Nacional de Investigaciones Oncológicas – CNIO, Madrid, Spain. [Lluch A] Medical Oncology Department, Hospital Clínico Universitario, Valencia, Spain. [Manso L] Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain. [Calvo I] Medical Oncology Department MD, Anderson Cancer Center Madrid, Madrid, Spain. [Cortes J] International Breast Cancer Center Quiron Group, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
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Paclitaxel ,Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES] ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,General Physics and Astronomy ,Breast Neoplasms ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,General Biochemistry, Genetics and Molecular Biology ,Càncer de mama ,Breast cancer ,Medicaments antibacterians - Ús terapèutic ,Humans ,Other subheadings::/therapeutic use [Other subheadings] ,Medicina personalitzada ,Precision Medicine ,neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES] ,Multidisciplinary ,Otros calificadores::/uso terapéutico [Otros calificadores] ,acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS] ,Cyclin-Dependent Kinase 4 ,General Chemistry ,Genomics ,Personalized medicine ,Genòmica ,Mama - Càncer - Tractament ,Female ,Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS] - Abstract
Breast cancer; Predictive markers; Proteomic analysis Cáncer de mama; Marcadores predictivos; Análisis proteómico Càncer de mama; Marcadors predictius; Anàlisi proteòmic Precision oncology research is challenging outside the contexts of oncogenic addiction and/or targeted therapies. We previously showed that phosphoproteomics is a powerful approach to reveal patient subsets of interest characterized by the activity of a few kinases where the underlying genomics is complex. Here, we conduct a phosphoproteomic screening of samples from HER2-negative female breast cancer receiving neoadjuvant paclitaxel (N = 130), aiming to find candidate biomarkers of paclitaxel sensitivity. Filtering 11 candidate biomarkers through 2 independent patient sets (N = 218) allowed the identification of a subgroup of patients characterized by high levels of CDK4 and filamin-A who had a 90% chance of achieving a pCR in response to paclitaxel. Mechanistically, CDK4 regulates filamin-A transcription, which in turn forms a complex with tubulin and CLIP-170, which elicits increased binding of paclitaxel to microtubules, microtubule acetylation and stabilization, and mitotic catastrophe. Thus, phosphoproteomics allows the identification of explainable factors for predicting response to paclitaxel. M.Q.F. is a recipient of the following grants: AES – PI16/00354 and AES – PI 19/00454 funded by the ISCIII and co-funded by the European Regional Development Fund (ERDF), and B2017/BMD3733 (Immunothercan-CM) – Call for Coordinated Research Groups from the Madrid Region – Madrid Regional Government – ERDF funds. R.C. is a recipient of the ISCIII grant PI17/01865, funded by the ISCIII and co-funded by the European Regional Development Fund (ERDF). Boehringer-Ingelheim contributed with a research grant to this project. This study was also funded by a donation from CRIS Contra el Cancer Foundation.
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- 2022
206. Discovery, Optimization, and Evaluation of Selective CDK4/6 Inhibitors for the Treatment of Breast Cancer
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Weijiao Chen, Minghui Ji, Hao Cheng, Mingming Zheng, Fei Xia, Wenjian Min, Huanaoyu Yang, Xiao Wang, Liping Wang, Lijuan Cao, Kai Yuan, and Peng Yang
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Drug Discovery ,Molecular Medicine ,Humans ,Cyclin-Dependent Kinase 4 ,Female ,Breast Neoplasms ,Cyclin-Dependent Kinase 6 ,Protein Kinase Inhibitors - Abstract
Breast cancer is the most common tumor in women, and selective cyclin-dependent kinase (CDK) 4/6 inhibitors played an important role in the treatment of breast cancer. Therefore, discovering selective CDK4/6 inhibitors with great safety and potent efficacy is beneficial for the breast cancer treatment. In our work, the lead compound
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- 2022
207. High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer
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Stefan Michiels, Cristina Saura, Cristina Viaplana, Marta Palafox, Abel Gonzalez-Perez, Alejandra Bruna, Paolo Nuciforo, Marta Guzman, Arribas Joaquín, Meritxell Bellet, Alicia García-Sanz, Violeta Serra, Faye Su, Olga Rodriguez, Nuria Lopez-Bigas, Analia Azaro, Monica Arnedos, Javier Hernández-Losa, Maurizio Scaltriti, Mafalda Oliveira, Laia Monserrat, Marta Capelán, Maria Teresa Herrera-Abreu, Carlos Caldas, Guillermo Villacampa, Leonardo Mina, Judit Grueso, Chandra S. Verma, Srinivasaraghavan Kannan, Robert Clarke, Nusaibah Ibrahimi, R. Dienstmann, Andreu Ódena, Nicholas C. Turner, Fara Brasó-Maristany, Aleix Prat, Mònica Sánchez-Guixé, Kui Lin, Gonzalez-Perez, Abel [0000-0002-8582-4660], Oliveira, Mafalda [0000-0001-9152-8799], Ibrahimi, Nusaibah [0000-0003-4537-0323], Kannan, Srinivasaraghavan [0000-0002-9539-5249], Sánchez-Guixé, Mònica [0000-0002-9430-4413], Hernández, Javier [0000-0003-1526-3201], Clarke, Robert B [0000-0001-5407-3123], Caldas, Carlos [0000-0003-3547-1489], Arribas, Joaquín [0000-0002-0504-0664], Michiels, Stefan [0000-0002-6963-2968], Turner, Nicholas C [0000-0001-8937-0873], Prat, Aleix [0000-0003-2377-540X], Nuciforo, Paolo [0000-0003-1380-0990], Lopez-Bigas, Nuria [0000-0003-4925-8988], Scaltriti, Maurizio [0000-0002-5522-1447], Saura, Cristina [0000-0001-8296-5065], Serra, Violeta [0000-0001-6620-1065], Apollo - University of Cambridge Repository, Institut Català de la Salut, [Palafox M, Monserrat L, Òdena A, Sánchez-Guixé M, Rodríguez O, Guzmán M, Grueso J] Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Bellet M, Bellet M, Capelán M, Azaro A, Saura C] Breast Cancer and Melanoma Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Villacampa G, Viaplana C, Dienstmann R] Oncology Data Science Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Gonzalez-Perez A] Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain. Research Program on Biomedical Informatics, Universitat Pompeu Fabra, Barcelona, Spain. [Hernández J] Grup de Recerca de Patologia Molecular Translacional, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Arribas J] CIBERONC, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Growth Factors Laboratory, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. [Nuciforo P] Molecular Oncology Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Serra V] Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. CIBERONC, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
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endocrine system ,Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm [PHENOMENA AND PROCESSES] ,endocrine system diseases ,Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES] ,Ubiquitin-Protein Ligases ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,General Physics and Astronomy ,Antineoplastic Agents ,Breast Neoplasms ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,Predictive markers ,Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors [CHEMICALS AND DRUGS] ,General Biochemistry, Genetics and Molecular Biology ,Càncer de mama ,Phosphatidylinositol 3-Kinases ,Text mining ,Breast cancer ,Er breast cancer ,Medicine ,Humans ,Cancer models ,neoplasms ,Protein Kinase Inhibitors ,Resistència als medicaments ,fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos [FENÓMENOS Y PROCESOS] ,neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES] ,Multidisciplinary ,Manchester Cancer Research Centre ,acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas [COMPUESTOS QUÍMICOS Y DROGAS] ,business.industry ,ResearchInstitutes_Networks_Beacons/mcrc ,Inhibitor resistance ,Cyclin-Dependent Kinase 4 ,General Chemistry ,Cyclin-Dependent Kinase 6 ,Proteïnes quinases - Inhibidors ,Retinoblastoma Binding Proteins ,Receptors, Estrogen ,Drug Resistance, Neoplasm ,Drug resistance ,Mama - Càncer - Tractament ,Cancer research ,Female ,business ,Biomarkers - Abstract
CDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n = 37) and estrogen receptor-positive breast cancer cell lines, as well as reduced response of early and advanced breast cancer patients to CDK4/6 inhibitors (n = 89). We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome. Combination of the CDK4/6 inhibitor ribociclib with the PI3K inhibitor alpelisib showed antitumor activity in estrogen receptor-positive non-basal-like breast cancer patient-derived xenografts, independently of PIK3CA, ESR1 or RB1 mutation, also in drug de-escalation experiments or omitting endocrine therapy. Our results offer insights into predicting primary/acquired resistance to CDK4/6 inhibitors and post-progression therapeutic strategies. This study has been supported by the Susan G. Komen Foundation (CCR15330331) and by the Catalan Agency AGAUR (2017 SGR 540) [to V.S.]. V.S. received funds from the Instituto de Salud Carlos III: grants PI13/01714, CP14/00228, MV15/00041, CPII19/00033 and PI20/00892. M.P. received a Juan de la Cierva Grant from the Ministerio de Economía y Competitividad (FJCI-2015-25412), L.Mo. a grant from FI-AGAUR (2019 FI_B 01199), F.B-M. a grant from the Fundación Científica Asociación Española Contra el Cáncer (AECC_Postdoctoral17-1062) and M.S-G, a Marie Slodowska-Curie Innovative Training Networks PhD fellowship (H2020-MSCA-ITN-2015_675392). This work was supported by Breast Cancer Research Foundation (BCRF-19-08), Instituto de Salud Carlos III Project Reference number AC15/00062 and the EC under the framework of the ERA-NET TRANSCAN-2 initiative co-financed by FEDER, Instituto de Salud Carlos III (CB16/12/00449 and PI19/01181) and Asociación Española Contra el Cáncer (to J.A.). R.B.C. laboratory is supported by Breast Cancer Now (grant numbers: MAN-Q1 and MAN-Q2), NIHR Manchester Biomedical Research Centre (IS-BRC-1215-20007) and EdiREX Horizon 2020 grant No.731105. The xenograft program in the C.C. laboratory is supported by Cancer Research UK and also received funding from an EU H2020 Network of Excellence (EuroCAN). This work has been supported by NIH grants P30 CA008748 and RO1CA190642-01, the CDMRP grant BC171535P1, and the Breast Cancer Research Foundation [to M.S.]. A.P. received funds from Instituto de Salud Carlos III—PI16/00904 and PI19/01846, Breast Cancer Now—2018NOVPCC1294, Breast Cancer Research Foundation-AACR Career Development Awards for Translational Breast Cancer Research 19-20-26-PRAT, Fundació La Marató TV3 201935-30, the European Union’s Horizon 2020 research and innovation program H2020-SC1-BHC-2018-2020. IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from the Spanish Ministry of Economy and Competitiveness (MINECO; Government of Spain) and is supported by CERCA (Generalitat de Catalunya). C. S. Verma reports grants from MSD International and grants from Ipsen outside the submitted work.
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- 2022
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208. CDK4/6 Inhibitors as Upfront Treatment in a Patient with Breast Cancer Presenting with a Clinical Critic Situation: A Case Report and Review of the Literature
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Giada, Targato, Lucia, Bortot, Arianna, Dri, Marta, Bonotto, Alessandro Marco, Minisini, Gianpiero, Fasola, and Mauro, Mansutti
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Humans ,Cyclin-Dependent Kinase 4 ,Female ,Breast Neoplasms ,Molecular Targeted Therapy ,Protein Kinase Inhibitors ,Aged - Abstract
CDK4/6 inhibitors have revolutionized the treatment algorithm of luminal metastatic breast cancer, becoming the recommended first-line therapy in association with endocrine therapy. However, due to its theoretically greater and more rapid tumor shrinkage, the upfront use of chemotherapy is considered in some clinical situations like visceral crisis. At the state of the art level, a paucity of data is available about the use of CDK4/6 inhibitors in patients presenting with visceral crisis or with life-threatening conditions since this population was historically excluded from clinical trials. In addition, data regarding direct comparison between combinations of chemotherapy and CDK4/6 inhibitors in terms of efficacy, rapidity of responses and long-term outcomes are lacking. We report the case of a 68-year-old woman with luminal metastatic breast cancer presenting at diagnosis with a critical and potentially life-threatening condition. The patient was treated with first-line Abemaciclib plus letrozole and achieved a rapid partial response with sudden clinical stabilization. Although the patient did not technically present with a visceral crisis, this case presentation also endorsed the upfront use of CDK4/6 inhibitor combinations in critical clinical situations in the absence of severe organ dysfunction and after multidisciplinary discussion.
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- 2022
209. APOBEC Mutational Signatures in Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancers Are Associated With Poor Outcomes on CDK4/6 Inhibitors and Endocrine Therapy
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Sarah Sammons, Kira Raskina, Natalie Danziger, Laura Alder, Alexa B. Schrock, Jeffrey M. Venstrom, Keith L. Knutson, E. Aubrey Thompson, Kim McGregor, Ethan Sokol, and Saranya Chumsri
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Cancer Research ,Oncology ,Receptors, Estrogen ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Humans ,Cyclin-Dependent Kinase 4 ,Breast Neoplasms ,Cyclin-Dependent Kinase 6 ,APOBEC Deaminases ,Immune Checkpoint Inhibitors ,United States - Abstract
PURPOSE APOBEC mutagenesis underlies somatic evolution and accounts for tumor heterogeneity in several cancers, including breast cancer (BC). In this study, we evaluated the characteristics of a real-world cohort for time-to-treatment discontinuation (TTD) and overall survival on CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) and immune checkpoint inhibitors. METHODS Comprehensive genomic profiling results from 29,833 BC samples were analyzed for tumor mutational burden and APOBEC signatures. For clinical outcomes, a deidentified nationwide (United States–based) BC Clinico-Genomic Database (CGDB) was evaluated with log-rank and Cox models. Patients with hormone receptor–positive (HR+) human epidermal growth factor receptor 2–negative (HER2–) BC who received first-line ET and CDK4/6i were included. Eligible patients from Mayo Clinic and Duke University were HR+ HER2– BC with sequencing data between September 2013 and July 2020. RESULTS Of 29,833 samples sequenced, 7.9% were APOBEC+ with a high rate in invasive lobular carcinoma (16.7%) and in metastatic tumors (9.7%) relative to locally biopsied BC (4.3%; P < .001). In CGDB, 857 patients with HR+ HER2– BC received ET plus CDK4/6i in the first line. APOBEC+ patients had significantly shorter TTD on ET plus CDK4/6i than APOBEC– patients, 7.8 (95% CI, 4.3 to 14.6) versus 12.4 months (95% CI, 11.2 to 14.1; hazard ratio, 1.6; 95% CI, 1.03 to 2.39; P = .0036). Clinical benefit to immune checkpoint inhibitors was observed in HR+ HER2–, APOBEC+, tumor mutational burden–high patients, with four of nine CGDB patients (TTD 0.3-11.3 months) and four of six patients in Duke/Mayo cohorts (TTD 0.9-40.5 months) with a TTD of ≥ 3 months. CONCLUSION APOBEC+ HR+ HER2– patients had shorter TTD on first-line ET plus CDK4/6i relative to APOBEC– patients. Further research is needed to optimize the treatment of APOBEC+ HR+ HER2– BC and to investigate the efficacy of immunotherapeutic strategies in this population.
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- 2022
210. CDK4/6 initiates Rb inactivation and CDK2 activity coordinates cell-cycle commitment and G1/S transition
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Sungsoo, Kim, Alessandra, Leong, Minah, Kim, and Hee Won, Yang
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Multidisciplinary ,Cyclins ,Cell Cycle ,Cyclin-Dependent Kinase 2 ,CDC2-CDC28 Kinases ,Cyclin-Dependent Kinase 4 ,Cell Cycle Proteins ,Phosphorylation ,Protein Serine-Threonine Kinases ,Retinoblastoma Protein ,Cyclin-Dependent Kinases - Abstract
External signaling controls cell-cycle entry until cells irreversibly commit to the cell cycle to ensure faithful DNA replication. This process is tightly regulated by cyclin-dependent kinases (CDKs) and the retinoblastoma protein (Rb). Here, using live-cell sensors for CDK4/6 and CDK2 activities, we propose that CDK4/6 initiates Rb inactivation and CDK2 activation, which coordinates the timing of cell-cycle commitment and sequential G1/S transition. Our data show that CDK4/6 activation induces Rb inactivation and thereby E2F activation, driving a gradual increase in CDK2 activity. We found that rapid CDK4/6 inhibition can reverse cell-cycle entry until CDK2 activity reaches to high levels. This suggests that high CDK2 activity is required to initiate CDK2-Rb positive feedback and CDK4/6-indpendent cell-cycle progression. Since CDK2 activation also facilitates initiation of DNA replication, the timing of CDK2-Rb positive feedback is coupled with the G1/S transition. Our experiments, which acutely increased CDK2 activity by cyclin E1 overexpression, indicate that cells commit to the cell cycle before triggering DNA replication. Together, our data suggest that CDK4/6 inactivates Rb to begin E2F and CDK2 activation, and high CDK2 activity is necessary and sufficient to generate a bistable switch for Rb phosphorylation before DNA replication. These findings highlight how cells initiate the cell cycle and subsequently commit to the cell cycle before the G1/S transition.
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- 2022
211. Rapid Capillary Electrophoresis Method for Simultaneous Determination of Abemaciclib, Ribociclib, and Palbociclib in Pharmaceutical Dosage Forms: A Green Approach
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Zvonimir Mlinarić, Lu Turković, Iva Begović, Biljana Nigović, and Miranda Sertić
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Organic Chemistry ,Pharmaceutical Science ,Cyclin-Dependent Kinase 4 ,Aminopyridines ,Electrophoresis, Capillary ,CDK4/6 inhibitors ,abemaciclib ,ribociclib ,palbociclib ,breast cancer ,green chemistry ,capillary electrophoresis ,Analytical Chemistry ,Pharmaceutical Preparations ,Chemistry (miscellaneous) ,Drug Discovery ,Molecular Medicine ,Benzimidazoles ,Physical and Theoretical Chemistry ,Protein Kinase Inhibitors - Abstract
Advances in the treatment of HR+/HER2- breast cancer phenotype have been made with the introduction of abemaciclib, ribociclib, and palbociclib, inhibitors of cyclin D dependent kinases 4 and 6 (CDK4/6). Here, a novel, fast, cheap, and green CE method for the simultaneous determination of these three CDK4/6 inhibitors in less than 4 min is proposed for the first time. Separation was achieved by capillary zone electrophoresis in an acidic medium, in accordance with the structures of the analytes and their pKa values. The optimal pH of the running buffer was found to be 2.9. The optimal method conditions were 27.5 kV separation voltage, 30 °C, 5 s injection time under 50 mbar pressure, and 50 mM phosphate background buffer with benzimidazole as an internal standard. The developed method was validated with respect to robustness, selectivity, accuracy, precision, linearity, and limits of detection. The method was shown to be linear in the range of 10 to 100 µg mL−1 with correlation coefficients higher than 0.9981. A greenness assessment of the proposed method was performed, and the method was shown to be green. The validated method was successfully applied to pharmaceutical dosage forms of all CDK4/6 inhibitors.
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- 2022
212. Synergistic Antitumor Effect of Taxanes and CDK4/6 Inhibitor in Lung Cancer Cells and Mice Harboring KRAS Mutations
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Min Young Kim, Jeong-Oh Kim, Jin-Hyoung Kang, Jung-Young Shin, and Kyoung-Hwa Son
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Cancer Research ,Lung Neoplasms ,Aminopyridines ,Antineoplastic Agents ,Apoptosis ,medicine.disease_cause ,Flow cytometry ,Proto-Oncogene Proteins p21(ras) ,Mice ,chemistry.chemical_compound ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Lung cancer ,Cytotoxicity ,Cell Proliferation ,medicine.diagnostic_test ,Cell growth ,Cell Cycle ,Cyclin-Dependent Kinase 4 ,Drug Synergism ,Cyclin-Dependent Kinase 6 ,General Medicine ,medicine.disease ,Xenograft Model Antitumor Assays ,Oncology ,Paclitaxel ,chemistry ,Mutation ,Cancer research ,Benzimidazoles ,Taxoids ,KRAS ,Signal Transduction - Abstract
Background/aim LY2835219 (LY), a novel CDK4/6 inhibitor, prevents cell proliferation through G1 arrest. Docetaxel (DTX) and paclitaxel (PTX) are cytotoxic drugs targeting tubulin-mediated apoptotic cell death via G2/M arrest. We evaluated the antitumor effects of DTX/PTX and LY individually and in combination in lung adenocarcinoma cells with or without KRAS mutations and xenograft mice harboring KRAS mutations. Materials and methods We investigated in vitro/in vivo changes in signaling molecules and analyzed cell proliferation, cycle, and apoptosis via flow cytometry and western blotting. Results LY cytotoxicity was dose-dependent and varied with KRAS mutation status. DTX→LY showed synergistic cytotoxicity regardless of KRAS mutation. Furthermore, the synergistic effect of PTX→LY was significantly greater than that of PTX+LY. DTX→LY remarkably reduced the number of G0/G1 cells and increased the number of G2/M arrested cells, resulting in an increase in apoptosis and subG1 cells. Conclusion DTX→LY has synergistic antitumor effect in lung cancer cells and xenograft mice regardless of KRAS mutation.
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- 2021
213. Identification of genes and pathways leading to metastasis and poor prognosis in melanoma
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Yun Wang, Xin Zhang, Guan Jiang, and Wandong Wang
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signaling pathway ,Aging ,Skin Neoplasms ,Databases, Factual ,Metastasis ,Phosphatidylinositol 3-Kinases ,microRNA ,melanoma ,medicine ,Humans ,Neoplasm Metastasis ,Survival rate ,Gene ,Survival analysis ,biology ,Melanoma ,Cyclin-Dependent Kinase 2 ,Cyclin-dependent kinase 2 ,regulatory analysis ,Computational Biology ,Cyclin-Dependent Kinase 4 ,bioinformatics ,Cell Biology ,Prognosis ,medicine.disease ,Survival Analysis ,MicroRNAs ,Cancer research ,biology.protein ,Signal transduction ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,Research Paper - Abstract
Melanoma causes the highest mortality rate among all skin cancers. However, the underlying molecular mechanisms leading to metastasis and poor prognosis in melanoma have not been fully elucidated. In this study, the differentially expressed genes (DEGs) related to metastasis in melanoma were screened out. The results of gene annotation was combined with The Cancer Genome Atlas (TCGA) database. The microRNA (miRNA) network that regulates key genes and their correlation with BRAFV600E was preliminarily analyzed. Cell and molecular biology experiments were conducted to verify the results of bioinformatics analysis. Results showed that the PI3K-Akt signaling pathway contained the key genes CDK2, CDK4, KIT, and Von Willebrand factor. Survival analysis showed that high expression of the four key genes significantly reduced the survival rate of patients with melanoma. Correlation analysis showed that BRAFV600E may regulate the expression of the four key genes, and a total of 240 miRNAs may regulate this expression. Experiments showed that the inactivation of key genes inhibits the proliferation, migration, and invasion of melanoma. In conclusion, the PI3K-Akt signaling pathway and the four key genes promoted the proliferation, migration, and invasion of melanoma, and related to poor prognosis of patients with melanoma.
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- 2021
214. An Overview of the Treatment Efficacy and Side Effect Profile of Pharmacological Therapies in Asian Patients with Breast Cancer
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Yen-Shen Lu, Winnie Yeo, Yeon Hee Park, Yoon Sim Yap, Rebecca Cheng, Huiping Li, and Kenji Tamura
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Oncology ,Cancer Research ,medicine.medical_specialty ,Side effect ,medicine.medical_treatment ,Breast Neoplasms ,Review Article ,Neutropenia ,Phosphatidylinositol 3-Kinases ,Breast cancer ,Asian People ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Adverse effect ,Protein Kinase Inhibitors ,business.industry ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,medicine.disease ,Clinical trial ,Treatment Outcome ,Female ,Hormone therapy ,business ,Pharmacogenetics ,Tamoxifen ,medicine.drug - Abstract
Breast cancer (BC) among Asians accounts for ~ 40% of the global BC burden. Differences in BC risk, presentation, tumor biology, and response to treatment exist between Asian and non-Asian patients; however, Asian patients are often under-represented in clinical trials. This narrative review summarizes the efficacy and safety of pharmacological therapies for BC in Asian populations, with a focus on outcomes in Asian versus non-Asian patients treated with chemotherapy, hormone therapy, anti-human epidermal growth factor receptor-2 targeted therapies, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, mammalian target of rapamycin inhibitors, bone-targeted therapies, poly-ADP ribose polymerase, phosphoinositide 3-kinase, and checkpoint inhibitors. While most therapies have demonstrated comparable efficacy and safety in Asian and non-Asian patients with BC, differences that are largely attributed to pharmacogenetic variations between populations exist. Pharmacogenetic differences may contribute to a reduced clinical benefit of tamoxifen, whereas improved clinical outcomes have been reported with tyrosine kinase inhibitors and CDK4/6 inhibitors in Asian versus non-Asian patients with BC. In particular, Asian patients have an increased incidence of hematological toxicities, including neutropenia, although adverse events can be effectively managed using dose adjustments. Recent trials with CDK4/6 inhibitors have increased efforts to include Asians within study subsets. Future clinical trials enrolling higher numbers of Asian patients, and an increased understanding of differences in patient and tumor genetics between Asians and non-Asians, have the potential to incrementally improve the management of BC in Asian patients.
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- 2021
215. Cyclin-dependent kinase 4 upregulation mediates acquired resistance of dabrafenib plus trametinib in BRAF V600E-mutated lung cancer
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Yoshinobu Ohsaki, Kanako C. Hatanaka, Takaaki Sasaki, Noriko Hirai, Yutaka Hatanaka, Shunsuke Okumura, Yasuhiro Umekage, Yuji Uno, Yoshinori Minami, and Shinichi Chiba
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Trametinib ,biology ,business.industry ,Cyclin-dependent kinase 4 ,MEK inhibitor ,Cancer ,Dabrafenib ,medicine.disease ,Real-time polymerase chain reaction ,Oncology ,biology.protein ,Cancer research ,Medicine ,business ,Lung cancer ,neoplasms ,V600E ,medicine.drug - Abstract
Background Combination therapy with the B-Raf inhibitor, dabrafenib, and the MEK inhibitor, trametinib (DT) is commonly used to treat patients with B-Raf proto-oncogene, serine/threonine kinase V600E (BRAF V600E)-mutated non-small cell lung cancer (NSCLC). However, the mechanisms through which cancer develops DT resistance are unclear. Here, we investigated new mechanisms underlying acquired DT-resistant NSCLC with the BRAF V600E mutation. Methods We compared genomic signatures before and after DT treatment in patients with NSCLC. Results Two of four patients treated with DT developed carcinomatous pleuritis within 3 months. Target DNA sequencing and quantitative polymerase chain reaction (PCR) analyses revealed the increased expression level of cyclin-dependent kinase 4 (CDK4). We also found prominent protein expression of CDK4 after DT treatment. Induction of CDK4 expression in a cell line derived from a patient with the BRAF V600E mutation resulted in partial resistance to dabrafenib. Conclusions Our findings suggest a possible relationship between CDK4 upregulation and acquired resistance to DT therapy.
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- 2021
216. Targeting cyclin-dependent kinase 4/6 as a therapeutic approach for mucosal melanoma
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Zhiyuan Zhang, Chaoji Shi, Rong Zhou, Yong Han, and Shengming Xu
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Cancer Research ,Skin Neoplasms ,Dermatology ,Review Article ,Therapeutic approach ,Mice ,Breast cancer ,cyclin-dependent kinase 4/6 inhibitors ,Medicine ,Animals ,Humans ,mucosal melanoma ,neoplasms ,Melanoma ,biology ,business.industry ,Cyclin-dependent kinase 4 ,Kinase ,Mucosal melanoma ,Cyclin-Dependent Kinase 4 ,clinical trial ,Cyclin-Dependent Kinase 6 ,medicine.disease ,Prognosis ,Clinical trial ,Disease Models, Animal ,Oncology ,Cutaneous melanoma ,Cancer research ,biology.protein ,cyclin-dependent kinases ,Mouth Neoplasms ,business - Abstract
Mucosal melanoma is a rare but devastating subtype of melanoma which typically has a worse prognosis than other melanoma subtypes. Large-scale next-generation sequencing studies, including our recent research, have also proved that the molecular landscape and potential oncogenic drivers of mucosal melanoma remain distinct from that of cutaneous melanoma. Recently, a number of selective cyclin-dependent kinase 4 (CDK4)/6 inhibitors have been approved for clinical application in breast cancer or entered phase III clinical trial in other solid tumors. Additionally, we have revealed that the dysregulation of cell cycle progression, caused by CDK4 amplification, is a key genetic feature in half of mucosal melanoma and targeting of CDK4 in selected mucosal melanoma patients is a potentially promising direction for precision cancer treatment by using molecular-characterized mucosal melanoma patient-derived-xenograft models. This review summarizes the current literature regarding CDK4/6 dysregulation in mucosal melanoma, preclinical and clinical studies of CDK4/6 inhibitors and potential combinational strategies in treating mucosal melanoma.
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- 2021
217. Treatment of Retinoblastoma 1–Intact Hepatocellular Carcinoma With Cyclin‐Dependent Kinase 4/6 Inhibitor Combination Therapy
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Fumio Matsuda, Paing Linn, Seiji Yano, Sharad Kumar, Hiroshi Inoue, Chiaki Takahashi, Susumu Kohno, Nobuhiro Okada, Naoko Nagatani, Jindan Sheng, Kenichi Harada, Kana Teranishi, Nobuyuki Okahashi, Minako Yamamura, Shunsuke Kitajima, Hiroshi Shimizu, Shin-ichi Horike, Itsuki Ajioka, Sheng, Jindan, Kohno, Susumu, Okada, Nobuhiro, Okahashi, Nobuyuki, Teranishi, Kana, Matsuda, Fumio, Shimizu, Hiroshi, Linn, Paing, Nagatani, Naoko, Yamamura, Minako, Harada, Kenichi, Horike, Shin-ichi, Inoue, Hiroshi, Yano, Seiji, Kumar, Sharad, Kitajima, Shunsuke, Ajioka, Itsuki, and Takahashi, Chiaki
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0301 basic medicine ,Hepatoblastoma ,Carcinoma, Hepatocellular ,Cell Survival ,Pyridines ,Aminopyridines ,carcinoma ,In Vitro Techniques ,Xenopus Proteins ,Palbociclib ,medicine.disease_cause ,Retinoblastoma Protein ,Piperazines ,combination therapy ,Mice ,03 medical and health sciences ,Liver Neoplasms, Experimental ,0302 clinical medicine ,Cyclin-dependent kinase ,Animals ,Humans ,Medicine ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Hepatology ,biology ,Kinase ,Cyclin-dependent kinase 4 ,business.industry ,Liver Neoplasms ,I-Kappa-B Kinase ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Hep G2 Cells ,medicine.disease ,increased immunogenicity ,030104 developmental biology ,Purines ,biology.protein ,Cancer research ,Benzimidazoles ,030211 gastroenterology & hepatology ,KRAS ,Tumor Suppressor Protein p53 ,business ,Neoplasm Transplantation - Abstract
Background and Aims: Synthetic cyclin-dependent kinase (CDK) 4/6 inhibitors exert antitumor effects by forcing RB1 in unphosphorylated status, causing not only cell cycle arrest but also cellular senescence, apoptosis, and increased immunogenicity. These agents currently have an indication in advanced breast cancers and are in clinical trials for many other solid tumors. HCC is one of promising targets of CDK4/6 inhibitors. RB family dysfunction is often associated with the initiation of HCC; however, this is revivable, as RB family members are not frequently mutated or deleted in this malignancy. Approach and Results: Loss of all Rb family members in transformation related protein 53 (Trp53)−/− mouse liver resulted in liver tumor reminiscent of human HCC, and re-expression of RB1 sensitized these tumors to a CDK4/6 inhibitor, palbociclib. Introduction of an unphosphorylatable form of RB1 (RB7LP) into multiple liver tumor cell lines induced effects similar to palbociclib. By screening for compounds that enhance the efficacy of RB7LP, we identified an I kappa B kinase (IKK)β inhibitor Bay 11-7082. Consistently, RB7LP expression and treatment with palbociclib enhanced IKKα/β phosphorylation and NF-κB activation. Combination therapy using palbociclib with Bay 11-7082 was significantly more effective in hepatoblastoma and HCC treatment than single administration. Moreover, blockade of IKK–NF-κB or AKT pathway enhanced effects of palbociclib on RB1-intact KRAS Kirsten rat sarcoma viral oncogene homolog mutated lung and colon cancers. Conclusions: In conclusion, CDK4/6 inhibitors have a potential to treat a wide variety of RB1-intact cancers including HCC when combined with an appropriate kinase inhibitor. Refereed/Peer-reviewed
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- 2021
218. Circular RNA circSP3 promotes hepatocellular carcinoma growth by sponging microRNA-198 and upregulating cyclin-dependent kinase 4
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Molin Li, Hang Chen, Lulu Xia, and Ping Huang
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Male ,Aging ,Carcinoma, Hepatocellular ,proliferation ,migration ,miR-198 ,Downregulation and upregulation ,Cell Movement ,Circular RNA ,Cell Line, Tumor ,microRNA ,medicine ,Animals ,Humans ,Gene silencing ,HCC ,Cell Proliferation ,Mice, Inbred BALB C ,biology ,Cyclin-dependent kinase 4 ,Kinase ,Cell growth ,Liver Neoplasms ,Cyclin-Dependent Kinase 4 ,RNA, Circular ,circSP3 ,Cell Biology ,medicine.disease ,Xenograft Model Antitumor Assays ,digestive system diseases ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Hepatocellular carcinoma ,Cancer research ,biology.protein ,Female ,Research Paper - Abstract
As a new class of endogenous noncoding RNAs, circular RNAs (circRNAs), have been found to influence cell development and function by sponging microRNAs. MicroRNA (miR)-198 is downregulated in various cancers, including hepatocellular carcinoma (HCC). We therefore searched for dysregulated circRNAs that could sponge miR-198 in HCC. By analyzing relevant circRNA databases (circBase, TargetScan and CircInteractome), we found that the miR-198-binding circRNA hsa_circSP3 is upregulated in HCC. CircSP3 expression correlated negatively with miR-198 expression in HCC tissues. Dual luciferase reporter assays indicated that circSP3 bound to miR-198. CircSP3 overexpression in HCC cells induced expression of cyclin-dependent kinase 4, a target gene of miR-198. Silencing circSP3 inhibited HCC cell proliferation and migration by downregulating cyclin-dependent kinase 4, whereas inhibiting miR-198 reversed those effects. In vivo experiments confirmed that circSP3 promoted xenograft tumor growth. These data suggest that circSP3 may be a novel biomarker for HCC.
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- 2021
219. A mixed‐methods study of cyclin‐dependent kinase 4 and 6 inhibitor symptom burden and quality of life among metastatic breast cancer patients and providers
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Hatem Soliman, Heather S.L. Jim, Michael H. Antoni, Frank J. Penedo, Cathy D. Meade, Mika Kadono, Brandy Arredondo, Dinorah Martinez-Tyson, Ricardo Costa, and Laura B. Oswald
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0301 basic medicine ,Cancer Research ,Psychological intervention ,neoplasm metastasis ,0302 clinical medicine ,polycyclic compounds ,breast neoplasms ,Medicine ,Molecular Targeted Therapy ,skin and connective tissue diseases ,Fatigue ,RC254-282 ,Original Research ,Cyclin-Dependent Kinase Inhibitor Proteins ,Oncologists ,biology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Middle Aged ,Metastatic breast cancer ,Oncology ,030220 oncology & carcinogenesis ,patient‐reported outcomes measures ,Female ,Needs Assessment ,Adult ,medicine.medical_specialty ,Psycho-oncology ,03 medical and health sciences ,Quality of life (healthcare) ,Humans ,Radiology, Nuclear Medicine and imaging ,Patient Reported Outcome Measures ,neoplasms ,Aged ,Cyclin-dependent kinase 4 ,business.industry ,Symptom burden ,Clinical Cancer Research ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,medicine.disease ,Supportive interventions ,030104 developmental biology ,quality of life ,psycho‐oncology ,Family medicine ,biology.protein ,business ,qualitative research ,Qualitative research - Abstract
Background Cyclin‐dependent kinase 4 and 6 (CDK4/6) inhibitor targeted therapies dramatically improve survival outcomes for metastatic breast cancer (MBC), but they are associated with significant symptom burden that can impact patients’ health‐related quality of life (HRQOL) and treatment outcomes. This study is the first to describe CDK4/6 inhibitor symptoms from the lived perspectives of MBC patients taking CDK4/6 inhibitors and healthcare providers involved in MBC care. This study also explored patients’ symptom management and HRQOL concerns, and gathered feedback about developing supportive interventions for MBC. Methods MBC patients taking CDK4/6 inhibitors (N = 20) and MBC healthcare providers (N = 12) participated in semi‐structured interviews that were analyzed for qualitative themes. MBC patients completed surveys about HRQOL, symptoms, and unmet needs. Results Patient and provider perceptions of CDK4/6 inhibitor symptoms did not align with patients perceiving symptoms as more burdensome. Patients reported that supportive resources (e.g., support groups, blogs) that are not specific to MBC do not adequately meet their needs. Patients and providers were enthusiastic about developing supportive interventions specifically for MBC and offered considerations for designing such interventions. Conclusions Findings highlight differences in perceptions of CDK4/6 inhibitor symptom burden between MBC patients and providers. Results will inform the development of supportive interventions to assist MBC patients in managing CDK4/6 inhibitor symptom burden and maintaining HRQOL. Such interventions could also improve treatment outcomes., Metastatic breast cancer (MBC) patient and provider perceptions of symptoms associated with CDK4/6 inhibitor did not align, with patients perceiving symptoms as more burdensome. Patients reported that supportive resources (e.g., support groups, blogs) that are not specific to MBC do not adequately meet their needs, however patients and providers were enthusiastic about developing supportive interventions specifically for MBC and offered considerations for designing such interventions. Results will inform the development of supportive interventions to assist MBC patients in managing CDK4/6 inhibitor symptom burden and maintaining health‐related quality of life.
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- 2021
220. Progression after First-Line Cyclin-Dependent Kinase 4/6 Inhibitor Treatment: Analysis of Molecular Mechanisms and Clinical Data.
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Villa F, Crippa A, Pelizzoni D, Ardizzoia A, Scartabellati G, Corbetta C, Cipriani E, Lavitrano M, and Ardizzoia A
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- Humans, Female, Cyclin-Dependent Kinase 4, Cell Cycle, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Cyclin-Dependent Kinase 6, Breast Neoplasms drug therapy, Breast Neoplasms pathology
- Abstract
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6iss) are widely used in first-line metastatic breast cancer. For patients with progression under CDK4/6is, there is currently no standard treatment recommended at the category 1 level in international guidelines. The purpose of this article is to review the cellular mechanisms underlying the resistance to CDK4/6is, as well as treatment strategies and the clinical data about the efficacy of subsequent treatments after CDK4/6is-based therapy. In the first part, this review mainly discusses cell-cycle-specific and cell-cycle-non-specific resistance to CDK4/6is, with a focus on early and late progression. In the second part, this review analyzes potential therapeutic approaches and the available clinical data on them: switching to other CDK4/6is, to another single hormonal therapy, to other target therapies (PI3K, mTOR and AKT) and to chemotherapy.
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- 2023
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221. An Overview of the Safety Profile and Clinical Impact of CDK4/6 Inhibitors in Breast Cancer-A Systematic Review of Randomized Phase II and III Clinical Trials.
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Stanciu IM, Parosanu AI, and Nitipir C
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- Humans, Female, Progression-Free Survival, Cyclin-Dependent Kinase 4, Clinical Trials, Phase II as Topic, Breast Neoplasms drug therapy
- Abstract
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have transformed the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer over the last decade. These inhibitors are currently established as first- and second-line systemic treatment choices for both endocrine-sensitive and -resistant breast cancer populations alongside endocrine therapy (ET) or monotherapy. Data on targeted therapy continue to mature, and the number of publications has been constantly rising. Although these drugs have been demonstrated to prolong overall survival (as well as progression-free survival (PFS) in breast cancer patients), changing the paradigm of all current knowledge, they also cause important adverse events (AEs). This review provides the latest summary and update on the safety profile of the three CDK4/6 inhibitors, as it appears from all major phase II and III randomized clinical trials regarding palbociclib, ribociclib, and abemaciclib, including the most relevant 15 clinical trials.
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- 2023
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222. [Treatment strategies for patients with resistant advanced breast cancer to CDK4/6 inhibitors].
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Zheng QF and Wang SS
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- Humans, Female, Phosphatidylinositol 3-Kinases, Cyclin-Dependent Kinase 4, Breast Neoplasms drug therapy
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CDK4/6 inhibitors have become the standard of care for HR-positive, HER2-negative advanced breast cancer. However, there is still a lack of standard recommendations for the subsequent treatment of patients with CDK4/6 inhibitor resistance, especially those with primary resistance or rapid progression. Currently, appropriate treatment strategies included re-challenge of CDK4/6 inhibitors, combination with PI3K/AKT/mTOR inhibitors, new antibody drug conjugate (ADC), novel endocrine therapy drugs, and chemotherapy. In addition, many new targeted drugs and new combination treatment strategies are also being explored. In the future, precise treatment strategies based on biomarkers should be established, as well as the optimal sequence of use of different therapies.
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- 2023
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223. Repurposing of approved drugs for targeting CDK4/6 and aromatase protein using molecular docking and molecular dynamics studies.
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Yousif FA, Alzain AA, Alraih AM, and Ibraheem W
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- Female, Humans, Molecular Docking Simulation, Molecular Dynamics Simulation, Apomorphine, Drug Repositioning, Estrogens, Aromatase Inhibitors pharmacology, Cyclin-Dependent Kinase 4, Aromatase, Breast Neoplasms
- Abstract
Breast cancer is a leading cause of cancer-related morbidity and mortality worldwide, with the highest incidence among women. Among the various subtypes of breast cancer, estrogen-receptor positive (ER+) is the most diagnosed. Estrogen upregulates cyclin D1, which in turn promotes the activity of CDK4/6 and facilitates cell cycle progression. To address this, the first-line treatment for ER+ breast cancer focuses on inhibiting estrogen production by targeting aromatase, the enzyme responsible for the rate-limiting step in estrogen synthesis. Thus, combining CDK4/6 inhibitors with aromatase inhibitors has emerged as a crucial treatment strategy for this type of breast cancer. This approach effectively suppresses estrogen biosynthesis and controls uncontrolled cell proliferation, significantly improving overall survival rates and delayed disease progression. This study aimed to identify compounds that are likely to inhibit CDK4/6 and aromatase simultaneously by using a structure-based drug design strategy. 12,432 approved and investigational drugs were prepared and docked into the active site of CDK6 using HTVS and XP docking modes of Glide resulting in 277 compounds with docking scores ≤ -7 kcal/mol. These compounds were docked into aromatase enzyme using XP mode to give seven drugs with docking scores≤ -6.001 kcal/mol. Furthermore, the shortlisted drugs were docked against CDK4 showing docking scores ranging from -3.254 to -8.254 kcal/mol. Moreover, MM-GBSA for the top seven drugs was calculated. Four drugs, namely ellagic acid, carazolol, dantron, and apomorphine, demonstrated good binding affinity to all three protein targets CDK4/6 and aromatase. Specifically, they exhibited favourable binding free energy with CDK6, with values of -51.92, -53.90, -50.22, and -60.97 kcal/mol, respectively. Among these drugs, apomorphine displayed the most favourable binding free energy with all three protein targets. To further evaluate the stability of the interaction, apomorphine was subjected to a 100 ns molecular dynamics simulation with CDK6. The results indicated the formation of a stable ligand-protein complex. While the results obtained from the MM-GBSA calculation of the binding free energies of the MD conformations of apomorphine showed less favourable binding free energy compared to that obtained post-docking. All these computational findings will provide better structural insight for the development of CDK4/6 and aromatase multi-target inhibitors., Competing Interests: he authors have declared that no competing interests exist., (Copyright: © 2023 yousif et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2023
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224. Preparation and Evaluation of [ 18 F]AlF-NOTA-PBB for PET Imaging of Cyclin-dependent Kinase 4/6 in Tumors.
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Xiao D, Gan Q, Duan X, Wang Q, Jiang Y, Han P, and Zhang J
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- Animals, Mice, Cyclin-Dependent Kinase 4, Mice, Nude, Tissue Distribution, Positron-Emission Tomography, Chelating Agents, Neoplasms diagnostic imaging
- Abstract
Cyclin-dependent kinases (CDKs), especially cyclin-dependent kinase 4/6 (CDK4/6), have been targets for the development of specific tumor imaging agents. Palbociclib is a highly selective CDK4/6 inhibitor. In this study, to develop a novel
18 F-labeled palbociclib derivative for specific tumor imaging, we designed and synthesized a ligand (NOTA-PBB) consisting of palbociclib as the targeted pharmacophore and NOTA as the macrocyclic bifunctional chelator. The corresponding [18 F]AlF-NOTA-PBB complex was prepared with high radiochemical purity (98.4 ± 0.15%) and yield (58.7 ± 4.5%) within 35 min without requiring HPLC purification through a simple one-step18 F-labeling strategy of NOTA-AlF chelation chemistry. The radiotracer was lipophilic (log P = 0.095 ± 0.003) and had good stability in vitro and in vivo . The cellular uptake studies performed on the MCF-7 breast cancer cell line (ER-positive and HER2-negative) showed that radioactive uptake was blocked by preincubating with a molar dose of palbociclib and it had a nanomolar binding affinity to CDK4/6 (IC50 = 16.23 ± 1.84 nM), demonstrating a CDK4/6-mediated uptake mechanism. Its ex vivo biodistribution in nude mice-bearing MCF-7 tumors showed obvious tumor uptake and a high tumor/muscle ratio of [18 F]AlF-NOTA-PBB, and tumor uptake was inhibited with 100 μg of palbociclib, demonstrating specific binding to CDK4/6. Radioactivity accumulation in MCF-7 tumors was observed in PET imaging with [18 F]AlF-NOTA-PBB. Based on the results of this work, [18 F]AlF-NOTA-PBB has the promising capability as a CDK4/6-targeted tumor imaging agent.- Published
- 2023
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225. Efficacy of adjuvant CDK4/6 inhibitors in hormone receptor-positive breast cancer: a systematic review and meta-analysis.
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Ergun Y, Dogan M, Ucar G, Karacin P, and Karacin C
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- Humans, Female, Progression-Free Survival, Disease-Free Survival, Cyclin-Dependent Kinase 4, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cyclin-Dependent Kinase 6, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Receptor, ErbB-2, Breast Neoplasms drug therapy, Breast Neoplasms pathology
- Abstract
Background: The combination of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and standard endocrine therapy (ET) in the adjuvant treatment of hormone receptor (HR)-positive/HER2-negative breast cancer (BC) has yielded conflicting results. We performed a pooled analysis of the adjuvant efficacy of CDK4/6 inhibitors by including data from the NATALEE trial, the most recent trial on this topic., Methods: We searched major databases and congress proceedings until 7 June 2023 to identify randomized controlled trials (RCT) comparing adjuvant CDK4/6 inhibitor plus ET combination versus ET in HR-positive/HER2-negative early-stage BC., Results: Four RCTs involving a total of 17,749 patients were included. According to the pooled analysis of these four studies, significant improvement in invasive disease-free survival (iDFS) was observed with the addition of CDK4/6 inhibitors to standard ET (HzR: 0.81, 95% CI 0.67-0.97). IDFS benefit was irrespective from menopausal status, Ki-67 index, tumor grade, and previous chemotherapy. CDK4/6 inhibitors plus ET had a significant improvement in iDFS in stage 3 whereas there was a trend toward better iDFS in stage 2 (HzR for stage 3: 0.67, 95% CI 0.58-0.78; HzR for stage 2: 0.74, 95% CI 0.55-1.01)., Conclusions: Addition of CDK4/6 inhibitors to standard ET in the adjuvant treatment of HR-positive/HER2-negative early-stage BC improves iDFS.
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- 2023
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226. Development of PROTAC degrader probe of CDK4/6 based on DCAF16.
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Pu C, Liu Y, Deng R, Xu Q, Wang S, Zhang H, Luo D, Ma X, Tong Y, and Li R
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- Humans, Cell Proliferation, Cell Line, Tumor, Cell Cycle, Cell Division, Cyclin-Dependent Kinase 4, Triple Negative Breast Neoplasms metabolism
- Abstract
Treatment of breast cancer has greatly evolved during the last decades, but triple negative breast cancer (TNBC) with a higher degree of malignancy cannot be directly and effectively treated. Abnormal cell cycle is generally found in human breast cancer and other malignant tumors, and cyclin-dependent kinases (CDK) 4/6, a cell cycle-related regulatory nuclear protein, is deemed as an effective target for breast cancer treatment so far. Since DCAF16 E3 ligase is also mainly distributed in the nucleus, in this study, by combining Palbociclib and DCAF16 E3 ligase ligand KB02 with different linkers, a series of DCAF16 based CDK4/6 degraders were designed and synthesized. Among them, compound A4 showed potent inhibitory activity against CDK4/6, and decreased the level of CDK4/6 protein in MDA-MB-231 cells in a concentration- and time-dependent manner. Moreover, the toxicity of A4 in normal cells showed 7 times lower than that of Palbociclib, and A4 exhibits therapeutic potential in MDA-MB-231 xenograft models in vivo. These findings indicate that A4, as a novel CDK4/6 degrader based on DCAF16, is worthy of further investigating for the treatment of TNBC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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227. Faecal microbiota composition is related to response to CDK4/6-inhibitors in metastatic breast cancer: A prospective cross-sectional exploratory study.
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Schettini F, Fontana A, Gattazzo F, Strina C, Milani M, Cappelletti MR, Cervoni V, Morelli L, Curigliano G, Iebba V, and Generali D
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- Humans, Female, Cross-Sectional Studies, Prospective Studies, Progression-Free Survival, Receptor, ErbB-2 metabolism, Protein Kinase Inhibitors adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cyclin-Dependent Kinase 4, Breast Neoplasms pathology, Microbiota
- Abstract
Background: Cyclin-dependent kinase (CDK)4/6-inhibitors with endocrine therapy represent the standard of treatment of hormone receptor-positive(HR+)/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Gut microbiota seems to predict treatment response in several tumour types, being directly implied in chemotherapy resistance and development of adverse effects. No evidence is available on gut microbiota impact on efficacy of HR+ breast cancer treatment., Patients and Methods: We assessed the potential association among faecal microbiota and therapeutic efficacy of CDK4/6-inhibitors on 14 MBC patients classified as responders (R) and non-responders (NR) according to progression-free survival. A stool sample was collected at baseline and V3-V4 16S targeted sequencing was employed to assess its bacterial composition. Statistical associations with R and NR were studied., Results: No significant differences were observed between R and NR in terms of α-/β-diversity at the phylum and species level. Machine-learning (ML) algorithms evidenced four bacterial species as a discriminant for R (Bifidobacterium longum, Ruminococcus callidus) and NR (Clostridium innocuum, Schaalia odontolytica), and an area under curve (AUC) of 0.946 after Random Forest modelling. Network analysis evidenced two major clusters of bacterial species, named Species Interacting Groups (SIG)1-2, with SIG1 harbouring 75% of NR-related bacterial species, and SIG2 regrouping 76% of R-related species (p < 0.001). Cross-correlations among several patients' circulating immune cells or biomarkers and bacterial species' relative abundances showed associations with potential prognostic implications., Conclusions: Our results provide initial insights into the gut microbiota involvement in sensitivity and/or resistance to CDK4/6-inhibitors + endocrine therapy in MBC. If confirmed in larger trials, several microbiota manipulation strategies might be hypothesised to improve response to CDK4/6-inhibitors., Competing Interests: Declaration of Competing Interest FS declares travel expenses by Novartis and Gilead and personal fees for educational events by Novartis, Daiichy-Sankyo and Gilead. DG declares personal fees for educational events by Novartis, Lilly, Pfizer, Daiichy-Sankyo, Roche; research funds from Astrazeneca, Novartis and LILT. GC declares reports advisory/consulting fees from Seagen, Roche, Novartis, Eli Lilly, Daiichi Sankyo, AstraZeneca, Pfizer, Sanofi, Pierre Fabre and Gilead, and fees for non-CME services (e.g. speakers' bureaus) from Eli Lilly, Pfizer Inc and Daiichi Sankyo. The other authors have nothing to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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228. Safety profile of cyclin-dependent kinase (CDK) 4/6 inhibitors with concurrent radiation therapy: A systematic review and meta-analysis.
- Author
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Becherini C, Visani L, Caini S, Bhattacharya IS, Kirby AM, Nader Marta G, Morgan G, Salvestrini V, Coles CE, Cortes J, Curigliano G, de Azambuja E, Harbeck N, Isacke CM, Kaidar-Person O, Marangoni E, Offersen B, Rugo HS, Morandi A, Lambertini M, Poortmans P, Livi L, and Meattini I
- Subjects
- Humans, Female, Cyclin-Dependent Kinases, Cyclin-Dependent Kinase 4, Protein Kinase Inhibitors adverse effects, Cyclin-Dependent Kinase 6, Antineoplastic Combined Chemotherapy Protocols, Radiosurgery, Breast Neoplasms drug therapy, Breast Neoplasms radiotherapy
- Abstract
The cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the standard of care for hormone receptor-positive (HR + ) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer, improving survival outcomes compared to endocrine therapy alone. Abemaciclib and ribociclib, in combination with endocrine therapy, have demonstrated significant benefits in invasive disease-free survival for high-risk HR+/HER2- early breast cancer patients. Each CDK4/6i-palbociclib, ribociclib, and abemaciclib-exhibits distinct toxicity profiles. Radiation therapy (RT) can be delivered with a palliative or ablative intent, particularly using stereotactic body radiation therapy for oligometastatic or oligoprogressive disease. However, pivotal randomized trials lack information on concomitant CDK4/6i and RT, and existing preclinical and clinical data on the potential combined toxicities are limited and conflicting. As part of a broader effort to establish international consensus recommendations for integrating RT and targeted agents in breast cancer treatment, we conducted a systematic review and meta-analysis to evaluate the safety profile of combining CDK4/6i with palliative and ablative RT in both metastatic and early breast cancer settings., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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229. Dalpiciclib in advanced breast cancer: introducing CDK4/6 inhibitors as a first-line treatment might not be the best strategy.
- Author
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Hindié E
- Subjects
- Humans, Female, Cyclin-Dependent Kinase 4, Breast Neoplasms drug therapy
- Abstract
Competing Interests: I declare no competing interests.
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- 2023
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230. Dalpiciclib in advanced breast cancer: introducing CDK4/6 inhibitors as a first-line treatment might not be the best strategy - Author's reply.
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Xu B
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- Humans, Female, Cyclin-Dependent Kinase 4, Breast Neoplasms drug therapy
- Abstract
Competing Interests: BX reports receiving research grants from Hengrui, advisory fees from Novartis and Roche, and fees for serving on a speakers’ bureau from AstraZeneca, Pfizer, Roche, and Eisai.
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- 2023
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231. CDK4/6 Inhibition in the Metastatic Setting: Where Are We Headed?
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Sakach E, Keskinkilic M, Wood S, Canning M, and Kalinsky K
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- Humans, Female, Quality of Life, Oncogenes, Molecular Targeted Therapy, Receptor, ErbB-2, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Antineoplastic Combined Chemotherapy Protocols adverse effects, Breast Neoplasms drug therapy, Neoplasms, Second Primary
- Abstract
Opinion Statement: Hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER-2-) metastatic breast cancer (MBC) is the most common subtype of breast cancer. Due to therapeutic advances with molecularly targeted therapies, the prognosis for patients with metastatic disease has improved significantly. The advent of CDK4/6 inhibitors (CDK4/6i) has changed the treatment paradigm for patients with HR+HER2-MBC. CDK4/6i allowed for marked improvement in overall survival, delaying the time to chemotherapy initiation, and improved quality of life for our patients. Efforts are now focused on the best approach(es) for patients after progression on CDK4/6i. Can we further harness the benefit of CDK4/6i in novel combinations at the time of progression? Should we continue CDK4/6i or proceed other novel agents or endocrine therapies? As we advance our treatment strategies for HR+HER2-MBC, there is no longer a one-size-fits-all model, but instead a multifaceted and personalized approach lending to improved outcomes for our patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2023
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232. CDK2 and CDK4 targeted liensinine inhibits the growth of bladder cancer T24 cells.
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Jiang H, Zhu S, Wu B, Su Y, Wang Q, Lei Y, Shao Q, Gao Y, Gao K, and Wu G
- Subjects
- Humans, Molecular Docking Simulation, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Databases, Genetic, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase 4, Urinary Bladder Neoplasms drug therapy, Drugs, Chinese Herbal
- Abstract
Bladder cancer (BCa) is a urinary tumor with limited treatment options and high mortality. Liensinine (LIEN), a natural bisbenzylisoquinoline alkaloid, has shown excellent anti-tumor effects in numerous preclinical studies. However, the anti-BCa effect of LIEN remains unclear. To the best of our knowledge, this is the first study to investigate the molecular mechanism of LIEN in the management of BCa. First, we identified the treatment-related targets of BCa; those that repeatedly occur in more than two databases, including GeneCards, Online Mendelian Inheritance in Man, DisGeNET, Therapeutic Target Database, and Drugbank. The SwissTarget database was used to screen LIEN-related targets, and those with a probability >0 were possible LIEN targets. The prospective targets of LIEN in the treatment of BCa were then determined using a Venn diagram. Second, we discovered that the PI3K/AKT pathway and senescence mediated the anti-BCa action of LIEN by using GO and KEGG enrichment analysis to explore the function of LIEN therapeutic targets. A protein-protein interaction network was created using the String website, and six algorithms of the CytoHubba plug-in were then used in Cytoscape to assess the core targets of LIEN for the therapy of BCa. The outcomes of molecular docking and dynamics simulation demonstrated that CDK2 and CDK4 proteins were the direct targets of LIEN in the management of BCa, among which CDK2 was more stable in binding to LIEN than CDK4. Finally, in vitro experiments showed that LIEN inhibited the activity and proliferation of T24 cells. The expression of p-/AKT, CDK2, and CDK4 proteins progressively decreased, while the expression and fluorescence intensity of the senescence-related protein, γH2AX, gradually increased with increasing LIEN concentration in T24 cells. Therefore, our data suggest that LIEN may promote senescence and inhibit proliferation by inhibiting the CDK2/4 and PI3K/AKT pathways in BCa., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)
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- 2023
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233. Efficacy of combined targeted therapy with PI3K and CDK4/6 or PARP and WEE1 inhibitors in neuroblastoma cell lines.
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Lukoseviciute M, Holzhauser S, Pappa E, Mandal T, Dalianis T, and Kostopoulou ON
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- Child, Humans, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Phosphatidylinositol 3-Kinase, Cell Line, Tumor, Cell Proliferation, Cell Cycle Proteins metabolism, Protein-Tyrosine Kinases, Cyclin-Dependent Kinase 4, Phosphatidylinositol 3-Kinases, Neuroblastoma drug therapy
- Abstract
Neuroblastoma (NB), the most frequent solid extracranial tumor in children, is not always cured by current aggressive therapies that have notable adverse effects; therefore, novel treatments are necessary. Phosphoinositide 3‑kinase (PI3K) and fibroblast growth factor receptor inhibitors exhibit synergistic effect in NB cell lines. In the present study, mono‑ and combination therapy of the United States Food and Drug Administration‑approved PI3K, cyclin‑dependent kinase‑4/6 (CDK4/6), poly‑ADP‑ribose‑polymerase (PARP) and WEE1 G2 checkpoint kinase (WEE1) inhibitors (BYL719, PD‑0332991, BMN673 and MK‑1775, respectively), were used to treat NB cell lines SK‑N‑AS, SK‑N‑BE(2)‑C, SK‑N‑DZ, SK‑N‑FI and SK‑N‑SH and viability (assessed by WST‑1 assay), proliferation (incucyte analysis) and cell cycle (FACS) changes were assessed. Treatments with all single drugs presented dose‑-dependent responses with decreased viability and proliferation and combining BYL719 with PD‑0332991 or BMN673 with MK‑1775 resulted in additive or synergistic effects in most cell lines., except for SK‑N‑SH for the former and for SK‑N‑AS for the latter. Moreover, combining MK‑1775 and BMN673 decreased the numbers of cells in S phase to a greater extent than either drug alone, while when combining PD‑0332991 and BYL719 the observed effect was close to that of PD‑0332991 alone. To summarize, PI3K and CDK4/6 or PARP and WEE1 exhibited synergistic anti‑NB effects and lower doses of the inhibitors could be utilized, thereby potentially reducing adverse side effects.
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- 2023
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234. CDK4/6-MEK Inhibition in MPNSTs Causes Plasma Cell Infiltration, Sensitization to PD-L1 Blockade, and Tumor Regression.
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Kohlmeyer JL, Lingo JJ, Kaemmer CA, Scherer A, Warrier A, Voigt E, Raygoza Garay JA, McGivney GR, Brockman QR, Tang A, Calizo A, Pollard K, Zhang X, Hirbe AC, Pratilas CA, Leidinger M, Breheny P, Chimenti MS, Sieren JC, Monga V, Tanas MR, Meyerholz DK, Darbro BW, Dodd RD, and Quelle DE
- Subjects
- Mice, Humans, Animals, Plasma Cells metabolism, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Mitogen-Activated Protein Kinase Kinases, Cell Line, Tumor, Tumor Microenvironment, Cyclin-Dependent Kinase 4, Neurofibrosarcoma drug therapy
- Abstract
Purpose: Malignant peripheral nerve sheath tumors (MPNST) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting cyclin-dependent kinases 4 and 6 (CDK4/6), MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models., Experimental Design: Patient-matched MPNSTs and precursor lesions were examined by FISH, RNA sequencing, IHC, and Connectivity-Map analyses. Antitumor activity of CDK4/6 and MEK inhibitors was measured in MPNST cell lines, patient-derived xenografts (PDX), and de novo mouse MPNSTs, with the latter used to determine anti-PD-L1 response., Results: Patient tumor analyses identified CDK4/6 and MEK as actionable targets for MPNST therapy. Low-dose combinations of CDK4/6 and MEK inhibitors synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death, and decreased clonogenic survival of MPNST cells. In immune-deficient mice, dual CDK4/6-MEK inhibition slowed tumor growth in 4 of 5 MPNST PDXs. In immunocompetent mice, combination therapy of de novo MPNSTs caused tumor regression, delayed resistant tumor outgrowth, and improved survival relative to monotherapies. Drug-sensitive tumors that regressed contained plasma cells and increased cytotoxic T cells, whereas drug-resistant tumors adopted an immunosuppressive microenvironment with elevated MHC II-low macrophages and increased tumor cell PD-L1 expression. Excitingly, CDK4/6-MEK inhibition sensitized MPNSTs to anti-PD-L1 immune checkpoint blockade (ICB) with some mice showing complete tumor regression., Conclusions: CDK4/6-MEK inhibition induces a novel plasma cell-associated immune response and extended antitumor activity in MPNSTs, which dramatically enhances anti-PD-L1 therapy. These preclinical findings provide strong rationale for clinical translation of CDK4/6-MEK-ICB targeted therapies in MPNST as they may yield sustained antitumor responses and improved patient outcomes., (©2023 American Association for Cancer Research.)
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- 2023
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235. Comparative efficacy and safety of different combinations of three CDK4/6 inhibitors with endocrine therapies in HR+/HER-2 - metastatic or advanced breast cancer patients: a network meta-analysis.
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Liu Y, Wu J, Ji Z, Chen L, Zou J, Zheng J, Lin W, Cai J, Chen Y, Zheng D, Chen Y, and Li Z
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- Humans, Female, Fulvestrant, Network Meta-Analysis, Aromatase Inhibitors, Cyclin-Dependent Kinase 4, Breast Neoplasms drug therapy
- Abstract
Background: This network meta-analysis aimed to assess the comparative efficacy and safety of combinations involving three cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and endocrine therapies (ETs) in patients with metastatic or advanced breast cancer (BC) who are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-)., Methods: We initially identified relevant studies from previous meta-analyses and then conducted a comprehensive search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases to locate additional studies published between February 2020 and September 2021. Essential data were extracted, and a network meta-analysis was performed using R 4.1.1 software with a random-effects model. Furthermore, we assigned rankings to all available treatment combinations by calculating their cumulative probability., Results: Data analysis included ten reports from nine studies. Pooled results demonstrated that each treatment combination significantly reduced the hazard risk of progression-free survival (PFS) compared to treatment with an aromatase inhibitor (AI) or fulvestrant alone. However, there were no differences observed in PFS or overall survival (OS) among the different treatment combinations. Additionally, patients receiving palbociclib plus AI and abemaciclib plus AI or fulvestrant experienced more severe adverse events (AEs), with hazard ratios (HRs) of 10.83 (95% confidence interval [CI] = 2.3 to 52.51) and 4.8 (95%CI = 1.41 to 16.21), respectively. The HR for ribociclib plus AI was 9.45 (95%CI = 2.02 to 43.61), and the HR for palbociclib plus fulvestrant was 6.33 (95%CI = 1.03 to 39.86). Based on the ranking probabilities, palbociclib plus fulvestrant had the highest probability of achieving superior PFS (37.65%), followed by abemaciclib plus fulvestrant (28.76%). For OS, ribociclib plus fulvestrant ranked first (34.11%), with abemaciclib plus fulvestrant in second place (25.75%). In terms of safety, palbociclib plus AI (53.98%) or fulvestrant (51.37%) had the highest probabilities of being associated with adverse events., Conclusions: Abemaciclib plus fulvestrant or ribociclib plus AI appear to be effective and relatively safe for the treatment of HR+/HER2- metastatic or advanced BC patients. However, given the reliance on limited evidence, our findings require further validation through additional studies., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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236. CDK4/6 inhibitors, PI3K/mTOR inhibitors, and HDAC inhibitors as second-line treatments for hormone receptor-positive, HER2-negative advanced breast cancer: a network meta-analysis.
- Author
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Ji D, Luo Y, Wang J, Chen S, Lan B, Ma F, Xu B, and Fan Y
- Subjects
- Humans, Female, Phosphatidylinositol 3-Kinases, MTOR Inhibitors, Fulvestrant therapeutic use, Histone Deacetylase Inhibitors adverse effects, Network Meta-Analysis, Cyclin-Dependent Kinase 4, Phosphatidylinositol 3-Kinase, Breast Neoplasms drug therapy
- Abstract
Background: This study sought to compare the benefits and safety of agents including Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors, and histone deacetylase (HDAC) inhibitors as second-line treatments for these patients by conducting a comprehensive systematic review and network meta-analysis., Methods: The Medline, Embase and Cochrane Library databases were searched for randomized trials comparing CDK4/6 inhibitors, PI3K/mTOR inhibitors, or HDAC inhibitors vs. placebo with the addition of exemestane or fulvestrant as second-line treatments in patients with HR + advanced breast cancer up to December 16, 2021. Outcomes of interest were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), clinical benefit rate (CBR), and grade 3-4 adverse drug events (ADEs). The present study was conducted according to the Cochrane Collaboration and PRISMA statements. The overall effect was pooled using the random effects model., Results: Seventeen studies with a total of 9,100 participants were included in the current study. Compared with placebo plus fulvestrant, PFS was significantly improved by CDK4/6 inhibitor plus fulvestrant, mTOR inhibitor plus fulvestrant, mTOR inhibitor plus exemestane, and PI3K inhibitor plus fulvestrant, but not HDAC inhibitor plus exemestane. While mTOR inhibitor plus exemestane was the best regimen (SUCRA value 89.5%), the mTOR inhibitor plus exemestane regimen induced more severe adverse events (SAEs) than the HDAC inhibitor plus exemestane regimen [OR, 95% CI: 2.40 (1.40-4.10)]., Conclusion: mTOR inhibitor and CDK4/6 inhibitor-based regimens demonstrated superior clinical efficacy and comparable safety profiles as second-line treatment in patients with HR-positive, HER2-negative advanced breast cancer., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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237. Randomized Phase II Trial of Endocrine Therapy With or Without Ribociclib After Progression on Cyclin-Dependent Kinase 4/6 Inhibition in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: MAINTAIN Trial.
- Author
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Kalinsky K, Accordino MK, Chiuzan C, Mundi PS, Sakach E, Sathe C, Ahn H, Trivedi MS, Novik Y, Tiersten A, Raptis G, Baer LN, Oh SY, Zelnak AB, Wisinski KB, Andreopoulou E, Gradishar WJ, Stringer-Reasor E, Reid SA, O'Dea A, O'Regan R, Crew KD, and Hershman DL
- Subjects
- Humans, Female, Cyclin-Dependent Kinase 4, Prospective Studies, Receptor, ErbB-2 metabolism, Double-Blind Method, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cyclin-Dependent Kinase 6, Breast Neoplasms pathology
- Abstract
Purpose: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) improves progression-free survival (PFS) and overall survival (OS) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Although preclinical and clinical data demonstrate a benefit in changing ET and continuing a CDK4/6i at progression, no randomized prospective trials have evaluated this approach., Methods: In this investigator-initiated, phase II, double-blind placebo-controlled trial in patients with HR+/HER2- MBC whose cancer progressed during ET and CDK4/6i, participants switched ET (fulvestrant or exemestane) from ET used pre-random assignment and randomly assigned 1:1 to the CDK4/6i ribociclib versus placebo. PFS was the primary end point, defined as time from random assignment to disease progression or death. Assuming a median PFS of 3.8 months with placebo, we had 80% power to detect a hazard ratio (HR) of 0.58 (corresponding to a median PFS of at least 6.5 months with ribociclib) with 120 patients randomly assigned using a one-sided log-rank test and significance level set at 2.5%., Results: Of the 119 randomly assigned participants, 103 (86.5%) previously received palbociclib and 14 participants received ribociclib (11.7%). There was a statistically significant PFS improvement for patients randomly assigned to switched ET plus ribociclib (median, 5.29 months; 95% CI, 3.02 to 8.12 months) versus switched ET plus placebo (median, 2.76 months; 95% CI, 2.66 to 3.25 months) HR, 0.57 (95% CI, 0.39 to 0.85); P = .006. At 6 and 12 months, the PFS rate was 41.2% and 24.6% with ribociclib, respectively, compared with 23.9% and 7.4% with placebo., Conclusion: In this randomized trial, there was a significant PFS benefit for patients with HR+/HER2- MBC who switched ET and received ribociclib compared with placebo after previous CDK4/6i and different ET.
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- 2023
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238. Radiation Pneumonitis, Really? A Case of Pulmonary Toxicity from CDK4/6 Inhibitor.
- Author
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Hunt A, Haque W, Pino R, Farach A, Butler EB, and Teh BS
- Subjects
- Female, Humans, Aged, Lung, Oxygen, Cyclin-Dependent Kinase 4, Radiation Pneumonitis diagnosis, Radiation Pneumonitis etiology, Lung Neoplasms drug therapy, Lung Neoplasms radiotherapy, Lung Neoplasms complications
- Abstract
Background/aim: Radiation pneumonitis is a known complication of radiotherapy. It is also a rare complication of CDK4/6 inhibitors, and it can be difficult to differentiate the two. This is a report of a case of pulmonary toxicity from a CDK4/6 inhibitor, which was initially ascribed to radiation pneumonitis., Case Report: A 77-year-old female was diagnosed with pneumonitis after receiving radiation to the thoracic spine. She had also been treated with abemaciclib. Upon review, the patient's lung mean dose was 11.54 Gy with a V20 of 17.02%, and the area of pneumonitis was largely outside of the treatment field. Abemaciclib was ceased. The patient was started on supportive oxygen as well as steroids. She no longer required oxygen and she was discharged from the hospital. Radiation pneumonitis is largely correlated with the volume of lung radiated and dose of radiation to the lung. CDK4/6 inhibitor pulmonary toxicity, while rare, is possible and will likely become more frequent with increasing use of these agents., Conclusion: Patients receiving CDK4/6 inhibitors are at an increased risk for pneumonitis. It can be confused with radiation pneumonitis and must be included in the differential diagnosis., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
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- 2023
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239. Anti-hepatocellular carcinoma activity of the cyclin-dependent kinase inhibitor AT7519.
- Author
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Karaś K, Karwaciak I, Chałaśkiewicz K, Sałkowska A, Pastwińska J, Bachorz RA, and Ratajewski M
- Subjects
- Humans, Cyclin-Dependent Kinases, Gefitinib pharmacology, Gefitinib therapeutic use, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase 4, Carcinoma, Hepatocellular drug therapy, Liver Neoplasms drug therapy
- Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancerous tumors and one of the leading causes of death among cancer-related disorders. Chemotherapy is ineffective in HCC patients, and the number of drugs that are in use is limited. Thus, new molecules are needed that could increase the effectiveness of anti-HCC regimens. Here, we show that AT7519, a CDK inhibitor, exerts positive effects on HCC cells: it inhibits proliferation, migration and clonogenicity. Detailed analysis of the transcriptomes of cells treated with this compound indicated that AT7519 affects a substantial portion of genes that are associated with HCC development and progression. Moreover, we showed that the concomitant use of AT7519 with gefitinib or cabozantinib sensitized HCC cells to these drugs. Thus, our research indicates that AT7519 is worth considering in monotherapy for hepatocellular carcinoma patients or in combination with other drugs, e.g., gefitinib or cabozantinib., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
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- 2023
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240. The effect of low HER2 expression on treatment outcomes in metastatic hormone receptor positive breast cancer patients treated with a combination of a CDK4/6 inhibitor and endocrine therapy: A multicentric retrospective study.
- Author
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Caliskan Yildirim E, Atag E, Coban E, Umit Unal O, Celebi A, Keser M, Uzun M, Keskinkilic M, Tanrikulu Simsek E, Sari M, and Yavuzsen T
- Subjects
- Humans, Female, Retrospective Studies, Receptor, ErbB-2 metabolism, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Treatment Outcome, Cyclin-Dependent Kinase 4, Breast Neoplasms pathology
- Abstract
Background: CDK4/6 inhibitors combined with endocrine therapy have significantly improved treatment outcomes for metastatic hormone receptor-positive (HR+) breast cancer patients. However, the impact of low HER2 expression on treatment response and progression-free survival (PFS) remains unclear., Methods: This multicenter retrospective study included 204 HR+ breast cancer patients treated with a combination of CDK4/6 inhibitor and endocrine therapy. HER2-zero disease was detected in 138 (68%) and HER2-low disease in 66 (32%) patients. Treatment-related characteristics and clinical outcomes were analyzed, with a median follow-up of 22 months., Results: The objective response rate (ORR) was 72.7% in the HER2 low group and 66.6% in the HER2 zero group (p = 0.54). Median PFS was not significantly different between the HER2-low and HER2 zero groups (19 months vs.18 months, p = 0.89), although there was a trend toward longer PFS in the HER2-low group for first-line treatment (24 months progression-free survival rate 63% vs 49%). In recurrent disease, the median PFS was 25 months in the HER2-low group and 12 months in the HER2-zero group (p = 0.08), while in de novo metastatic disease, the median PFS was 18 months in the HER2-low group and 27 months in the HER2-zero group (p = 0.16). The order of CDK4/6 inhibitor use and the presence of visceral metastasis were identified as independent variables affecting PFS., Conclusion: Low HER2 expression did not significantly impact treatment response or PFS in HR+ breast cancer patients treated with a CDK4/6 inhibitor and endocrine therapy. Because of the conflicting results in the literature, further prospective studies are needed to evaluate the clinical significance of HER2 expression in HR+ breast cancer., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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241. Real-world treatment patterns of subsequent therapy after palbociclib in patients with advanced breast cancer in Japan.
- Author
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Sawaki M, Muramatsu Y, Togo K, and Iwata H
- Subjects
- Humans, Female, Japan, Pyridines therapeutic use, Piperazines, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cyclin-Dependent Kinase 4, Protein Kinase Inhibitors therapeutic use, Receptor, ErbB-2, Breast Neoplasms etiology
- Abstract
Purpose: The optimal treatment following endocrine therapy (ET) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) has not been established. We aimed to investigate treatment patterns and time to treatment failure (TTF) of subsequent therapy after palbociclib in a Japanese real-world setting., Methds: This retrospective observational study used de-identified data of patients with advanced breast cancer treated with palbociclib, using a nationwide claims database (April 2008 to June 2021). Measures included the type of subsequent therapies after palbociclib (endocrine-based therapy: ET alone, ET + CDK4/6i, and ET + mammalian target of rapamycin inhibitor [mTORi]; chemotherapy; chemotherapy + ET; and others) and their TTFs. The median TTF and 95% confidence interval (CI) were estimated using the Kaplan-Meier method., Results: Of 1170 patients treated with palbociclib, 224 and 235 received subsequent therapies after first- and second-line palbociclib treatment, respectively. Among them, 60.7% and 52.8% were treated with endocrine-based therapies as first subsequent therapy, including ET + CDK4/6i (31.2% and 29.8%, respectively). The median TTF (95% CI) of ET alone, ET + CDK4/6i, and ET + mTORi as first subsequent therapy after first-line palbociclib were 4.4 (2.8-13.7), 10.9 (6.5-15.6), and 6.1 (5.1-7.2) months, respectively. No apparent relationship between the treatment duration of prior ET + palbociclib and subsequent abemaciclib was observed., Conclusion: This real-world study revealed that one-third of the patients received sequential CDK4/6i after ET + palbociclib, and treatment duration of ET + CDK4/6i following ET + palbociclib was the longest among the treatment options. Further data are awaited to determine whether ET + targeted therapy with CDK4/6i and mTORi provides acceptable treatment options following ET + palbociclib., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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242. Cost-Effectiveness Analysis of Cyclin-Dependent Kinase 4/6 Inhibitor Palbociclib for Inoperable or Recurrent Breast Cancer.
- Author
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Shida T, Kaneko M, Ogura J, Sawada H, Hatakeyama S, Arakawa I, Yamaguchi H, and Inoue T
- Subjects
- Humans, Female, Fulvestrant therapeutic use, Cost-Effectiveness Analysis, Cyclin-Dependent Kinase 4, Breast Neoplasms drug therapy
- Abstract
Background: Palbociclib and endocrine therapy has been approved to treat hormone receptor-positive/human epidermal growth factor receptor 2-negative inoperable or recurrent breast cancer in Japan. However, this cotherapy imposes an economic burden on both patients and society because of its high cost. In this study, we assessed the cost-effectiveness of cotherapy with palbociclib and fulvestrant compared to fulvestrant monotherapy for inoperable or recurrent breast cancer., Methods: The three-state Markov model was built by taking into count health stats in inoperable or recurrent breast cancer. The clinical outcomes of the therapies were drawn from published randomized controlled trials. Total regimen cost was calculated from medical receipts of patients at the Yamagata University Hospital. The cost-effectiveness was evaluated by the incremental cost-effectiveness ratio(ICER), in case that it was below 400,000 Yen per month. Markov chain Monte Carlo simulation was performed to assess probability., Results: Acquisition cost of palbociclib and fulvestrant and fulvestrant monotherapy was 6,209,554 JPY and 780,870 JPY, and 25.7 and 22.8 months were achieved, respectively. ICER for the cotherapy was 1,847,721 JPY/quality adjusted life month(QALM)gained., Conclusions: The palbociclib and fulvestrant therapy provided better health outcomes than conventional fulvestrant monotherapy, but were costly and suggested to be less cost-effective.
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- 2023
243. Dual targeting of CDK4/6 and Bcl-2 exhibits a potent antitumor effect on mantle cell lymphoma.
- Author
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Che Y, Liu Y, Li Y, McIntosh JM, Jordan A, Yan F, Wang W, Nie L, Lee HH, Jin J, Yao Y, Zhao Z, Jiang VC, and Wang M
- Subjects
- Humans, Cyclin-Dependent Kinase 4, Lymphoma, Mantle-Cell drug therapy, Lymphoma, Mantle-Cell pathology
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- 2023
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244. CDK4/6 Inhibitor Resistance in Hormone Receptor-Positive Metastatic Breast Cancer: Translational Research, Clinical Trials, and Future Directions.
- Author
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Lee JS, Hackbart H, Cui X, and Yuan Y
- Subjects
- Humans, Female, Translational Research, Biomedical, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Cyclin-Dependent Kinase Inhibitor Proteins, Progression-Free Survival, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Breast Neoplasms pathology
- Abstract
The emergence of CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor-positive breast cancer. These agents have demonstrated significant clinical benefits in terms of both progression-free survival and overall survival. However, resistance to CDK4/6 inhibitors remains a challenge, limiting their long-term efficacy. Understanding the complex mechanisms driving resistance is crucial for the development of novel therapeutic strategies and the improvement of patient outcomes. Translational research efforts, such as preclinical models and biomarker studies, offer valuable insight into resistance mechanisms and may guide the identification of novel combination therapies. This review paper aims to outline the reported mechanisms underlying CDK4/6 inhibitor resistance, drawing insights from both clinical data and translational research in order to help direct the future of treatment for hormone receptor-positive metastatic breast cancer.
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- 2023
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245. Prognostic value of [18F]-FDG PET/CT in patients with meta-static breast cancer treated with cyclin-dependent inhibitors.
- Author
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Annovazzi A, Rea S, Maccora D, Pizzuti L, Ferretti G, Vici P, Cappuzzo F, and Sciuto R
- 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., 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 © 2023 Annovazzi, Rea, Maccora, Pizzuti, Ferretti, Vici, Cappuzzo and Sciuto.)
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- 2023
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- View/download PDF
246. [Advance on cyclin D1 and CDK4 in cutaneous melanoma].
- Author
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Guo RP, Yang LY, Zhao JF, and Su J
- Subjects
- Humans, Cyclin D1, Cyclin-Dependent Kinase 4, Melanoma, Cutaneous Malignant, Melanoma, Skin Neoplasms
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- 2023
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- View/download PDF
247. Social determinants of health and CDK4/6 inhibitor use and outcomes among patients with metastatic breast cancer.
- Author
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Sathe C, Accordino MK, DeStephano D, Shah M, Wright JD, and Hershman DL
- Subjects
- United States epidemiology, Humans, Aged, Female, Medicare, Retrospective Studies, Social Determinants of Health, Cyclin-Dependent Kinase 4, Breast Neoplasms drug therapy, Breast Neoplasms epidemiology, Leukopenia
- Abstract
Background: Survival outcomes in metastatic breast cancer (MBC) have improved due to novel agents such as CDK4/6 inhibitors (CDK4/6i). Nevertheless, Black patients and patients with lower socioeconomic status (SES) continue to bear a disproportionate mortality burden., Methods: We conducted a retrospective analysis of EHR-derived data from the Flatiron Health Database (FHD). A dataset was constructed to include Black/African-American (Black/AA) and White patients with hormone receptor (HR)-positive, HER2-negative MBC. Outcomes included CDK4/6i use (overall and first-line), and rates of leukopenia, dose reduction, and time on treatment for first-line CDK4/6i. Multivariable logistic regression was used to evaluate factors associated with use and outcomes., Results: A total of 6802 patients with MBC were included, of which 5187 (76.3%) received CDK4/6i. Of those, 3186 (61.4%) received CDK4/6i first-line. Overall, 86.7% of patients were categorized as White and 13.3% as Black/AA; 22.4% were > 75 years old; 12.6% were treated at an academic site; 3.3% had Medicaid insurance. In addition to advanced age and poorer performance status, lower use of CDK4/6i was associated with Black/AA vs White race (72.9% vs 76.8%; OR 0.83, 95% CI 0.70-0.99, p = 0.04) and Medicaid vs commercial insurance (69.6% vs 77.4%; OR: 0.68, 95% CI 0.49-0.95, p = 0.02). Odds of CDK4/6i use were twofold higher for patients treated at an academic center (p < 0.001). Rates of CDK4/6i-induced leukopenia and dose reductions did not differ significantly by race, insurance type, or treatment site. Time on CDK4/6i was significantly lower among Medicaid patients (395 days) than patients with commercial insurance (558 days) or Medicare (643 days) (p = 0.03)., Conclusion: This analysis of real-world data suggests that Black race and lower SES are associated with decreased CDK4/6i use. However, among patients treated with CDK4/6i, subsequent toxicity outcomes are similar. Efforts to ensure access to these life-prolonging medications are warranted., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2023
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248. CDK4/6 inhibitor modulating active and quiescent intestinal stem cells for prevention of chemotherapy-induced diarrhea.
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Xiang J, Wang H, Tao Q, Li W, Huang Y, Zhang Y, Yang L, and Zhang S
- Subjects
- Humans, Cell Differentiation, Stem Cells pathology, United Kingdom, Intestinal Mucosa pathology, Cyclin-Dependent Kinase 4, Diarrhea pathology, Antineoplastic Agents
- Abstract
Chemotherapy-induced diarrhea causes dehydration, debilitation, infection, and even death, but there are currently no Food and Drug Administration (FDA)-approved drugs for treatment of chemotherapy-induced diarrhea. It is generally believed that the timely regulation of intestinal stem cell (ISC) fate may provide a meaningful solution for intestinal injuries. However, the lineage plasticity of ISCs during and after chemotherapy remains poorly understood. Here, we demonstrated that palbociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, regulated the fate of active or quiescent ISCs, provided multilineage protection from the toxicity of several different chemotherapeutics, and accelerated gastrointestinal epithelium recovery. Consistent with in vivo results, we determined that palbociclib enhanced intestinal organoid and ex vivo tissue survival after chemotherapy. Lineage tracing studies have shown that palbociclib protects active ISCs marked by Lgr5 and Olfm4 during chemotherapy and unexpectedly activates quiescent ISCs marked by Bmi1 to immediately participate in crypt regeneration after chemotherapy. Furthermore, palbociclib does not decrease the efficacy of cytotoxic chemotherapy in tumor grafts. The experimental evidence suggests that the combination of CDK4/6 inhibitors with chemotherapy could reduce damage to the gastrointestinal epithelium in patients. © 2023 The Pathological Society of Great Britain and Ireland., (© 2023 The Pathological Society of Great Britain and Ireland.)
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- 2023
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249. Interstitial lung disease and CDK4/6 inhibitors in the treatment of breast cancer.
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Schlam I, Giordano A, and Tolaney SM
- Subjects
- Humans, Female, Protein Kinase Inhibitors adverse effects, Drug Interactions, Aminopyridines, Cyclin-Dependent Kinase 4, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Lung Diseases, Interstitial chemically induced
- Abstract
Introduction: CDK4/6 inhibitors have changed the treatment paradigm of many patients living with metastatic and early-stage high-risk hormone receptor (HR)-positive breast cancer. Even though patients and clinicians are aware and learning how to manage common adverse events, such as bone marrow suppression and gastrointestinal toxicities, there are less common and potentially severe adverse events, such as interstitial lung disease (ILD), that require special consideration., Areas Covered: In this narrative review, we discuss the incidence, mechanism, and treatment of CDK4/6 inhibitor associated ILD., Expert Opinion: CDK4/6 inhibitors in combination with endocrine therapy (ET) are standard treatment for HR-positive, HER2-negative metastatic breast cancer and for selected patients with early stage HR-positive breast cancer. Common toxicities of these medications are often controlled with dose reductions, dose interruptions, and/or prophylactic medications, such as antidiarrheals. However, there are a small subset of patients at risk for less common and potentially severe toxicities, such as ILD. Individualized risk should be considered, including underlying lung disease, thrombosis risk and drug-drug interactions, in order to counsel patients about the risk of ILD.
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- 2023
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250. Cyclin-dependent kinase 4/6 inhibitor treatment use in women treated for advanced breast cancer: Integrating ASCO/NCODA patient-centered standards in a community pharmacy.
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Marineau A, St-Pierre C, Lessard-Hurtubise R, David MÈ, Adam JP, and Chabot I
- Subjects
- Humans, Female, Letrozole therapeutic use, Fulvestrant therapeutic use, Cyclin-Dependent Kinase 4, Retrospective Studies, Protein Kinase Inhibitors, Patient-Centered Care, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms pathology, Pharmacies
- Abstract
Background: Outpatients treated with oral anti-cancer drugs, including selective cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), may benefit from a pharmacy practice setting adapted to support proper oral anti-cancer drug monitoring. This real-world study aimed to characterize patient-centered pharmacy practice aligned with American Society of Clinical Oncology (ASCO)/National Community Oncology Dispensing Association (NCODA) standards and to describe its impact on CDK4/6i treatment use., Methods: This retrospective study included women with confirmed hormone receptor-positive/human epidermal growth factor 2 negative locally advanced or metastatic breast cancer treated with either palbociclib, abemaciclib or ribociclib combined with letrozole or fulvestrant. Pharmacists collected patient characteristics, clinical activities, and treatment patterns using data from the pharmacy chart. CDK4/6i treatment adherence rates were estimated based on medication claims data. Time-to-treatment discontinuation, a proxy for time-to-event, was assessed using the Kaplan-Meier estimate., Results: Of the 195 patients assessed for eligibility, 65 were included in this study. The median observation duration was 13.6 months. An average of seven pharmaceutical care activities (range 2.8-21.7) per patient was documented for each treatment cycle. The mean proportion of days covered was 89.6%. The median time-to-treatment discontinuation was estimated at 44.2 months in patients treated with CDK4/6i + letrozole and 17.0 months in patients treated with CDK4/6i + fulvestrant. The average relative dose intensity was 85%, and the benefits of treatment were maintained regardless of the relative dose intensity levels., Conclusion: A structured patient-centered pharmacy practice model integrating the ASCO/NCODA patient-centered standards and ongoing communication with patients and healthcare providers ensure timely refills, close monitoring, and allows patients to achieve high adherence and persistence rates comparable to those reported in clinical trials.
- Published
- 2023
- Full Text
- View/download PDF
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