Sistema de Salut de Catalunya
Institut Català de la Salut
[Glaviano A] Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy. [Wander SA] Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. [Baird RD] Cancer Research UK Cambridge Centre, Hills Road, Cambridge CB2 0QQ, UK. [Yap KCH, Lam HY] Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. [Toi M] School of Medicine, Kyoto University, Kyoto, Japan. [Serra V] Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
Vall d'Hebron Barcelona Hospital Campus
2024-07-04T12:18:30Z
2024-07-04T12:18:30Z
2024-06-25
CDK4/6i resistance; Endocrine therapy; Breast cancer
Resistencia a CDK4/6i; Terapia endocrina; Cáncer de mama
Resistència a CDK4/6i; Teràpia endocrina; Càncer de mama
Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key molecules in the G1-to-S phase cell cycle transition and are crucial for the onset, survival, and progression of breast cancer (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation of tumor suppressor Rb and thus restrain susceptible BC cells in G1 phase. Three CDK4/6i are approved for the first-line treatment of patients with advanced/metastatic hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) BC in combination with endocrine therapy (ET). Though this has improved the clinical outcomes for survival of BC patients, there is no established standard next-line treatment to tackle drug resistance. Recent studies suggest that CDK4/6i can modulate other distinct effects in both BC and breast stromal compartments, which may provide new insights into aspects of their clinical activity. This review describes the biochemistry of the CDK4/6-Rb-E2F pathway in HR+ BC, then discusses how CDK4/6i can trigger other effects in BC/breast stromal compartments, and finally outlines the mechanisms of CDK4/6i resistance that have emerged in recent preclinical studies and clinical cohorts, emphasizing the impact of these findings on novel therapeutic opportunities in BC.
A.P.K. was supported by a grant from the Singapore Ministry of Education (MOE-T2EP30120–0016).
Article
Published version
English
Proteïnes quinases - Inhibidors - Ús terapèutic; Mama - Càncer - Tractament; Resistència als medicaments; DISEASES::Neoplasms::Neoplasms by Site::Breast Neoplasms; Other subheadings::Other subheadings::Other subheadings::/drug therapy; PHENOMENA AND PROCESSES::Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance; CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors; Other subheadings::Other subheadings::Other subheadings::/administration & dosage; ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias de la mama; Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia; FENÓMENOS Y PROCESOS::fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos; COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas; Otros calificadores::Otros calificadores::Otros calificadores::/administración & dosificación
Elsevier
Drug Resistance Updates;76
https://doi.org/10.1016/j.drup.2024.101103
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
