2026-04-17T02:50:41Zhttps://recercat.cat/oai/request

oai:recercat.cat:11351/93612025-09-30T02:08:04Zcom_2072_378070com_2072_378040com_2072_378071col_2072_378092col_2072_378097

High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer Palafox Sánchez, Marta Monserrat Vicente, Laia Antunes de Melo Oliveira, Ana Mafalda Òdena, Andreu Sanchez-Guixe, Monica Capelan Rodríguez, Marta Azaro Pedrazzoli, Analía Beatriz Rodriguez Ferreiro, Olga Guzman Torres, Marta Grueso Gragera, Judit Viaplana Donato, Cristina Hernandez Losa, Javier Arribas López, Joaquin Vicente Nuciforo, Paolo Giovanni Serra Elizalde, Violeta Villacampa Javierre, Guillermo Bellet Ezquerra, Meritxell Saura Manich, Cristina Dienstmann, Rodrigo Gonzalez-Perez, Abel Mama - Càncer - Tractament Proteïnes quinases - Inhibidors 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::Drug Resistance, Neoplasm CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors 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::resistencia a los antineoplásicos COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas Breast cancer; Cancer models; Predictive markers Cáncer de mama; Modelos de cáncer; Marcadores predictivos Càncer de pulmó; Models de càncer; Marcadors predictius 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. 2023-04-18T12:21:40Z 2023-04-18T12:21:40Z 2022-09-07 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Nature Communications;13 https://doi.org/10.1038/s41467-022-32828-6 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Nature Portfolio Scientia