High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer
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Published:2022-09-07
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Palafox Marta, Monserrat Laia, Bellet Meritxell, Villacampa Guillermo, Gonzalez-Perez AbelORCID, Oliveira MafaldaORCID, Brasó-Maristany Fara, Ibrahimi NusaibahORCID, Kannan SrinivasaraghavanORCID, Mina Leonardo, Herrera-Abreu Maria Teresa, Òdena Andreu, Sánchez-Guixé MònicaORCID, Capelán Marta, Azaro Analía, Bruna Alejandra, Rodríguez Olga, Guzmán Marta, Grueso Judit, Viaplana Cristina, Hernández JavierORCID, Su Faye, Lin Kui, Clarke Robert B.ORCID, Caldas CarlosORCID, Arribas JoaquínORCID, Michiels StefanORCID, García-Sanz Alicia, Turner Nicholas C.ORCID, Prat AleixORCID, Nuciforo PaoloORCID, Dienstmann Rodrigo, Verma Chandra S., Lopez-Bigas NuriaORCID, Scaltriti MaurizioORCID, Arnedos Monica, Saura CristinaORCID, Serra VioletaORCID
Abstract
AbstractCDK4/6 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference64 articles.
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