High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer
Marta Palafox, Laia Monserrat, Meritxell Bellet, Guillermo Villacampa, Abel González-Pérez, Mafalda Oliveira, Fara Brasó‐Maristany, Nusaïbah Ibrahimi, Srinivasaraghavan Kannan, Leonardo Mina, María Teresa Herrera-Abreu, Andreu Òdena, Mònica Sánchez-Guixé, Marta Capelán, Analía Azaro, Alejandra Bruna, Olga Rodríguez, Marta Guzmán, Judit Grueso, Cristina Viaplana, Javier Hernández‐Losa, Faye Su, Kui Lin, Robert B. Clarke, Carlos Caldas, Joaquı́n Arribas, Stefan Michiels, Alicia García‐Sanz, Nicholas C. Turner, Aleix Prat, Paolo Nucíforo, Rodrigo Dienstmann, Chandra Verma, Núria López-Bigas, Maurizio Scaltriti, Mónica Arnedos, Cristina Saura, Violeta Serra
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.