High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer

• Main Authors: Palafox, Marta, Monserrat, Laia, Bellet, Meritxell, Villacampa, Guillermo, Gonzalez-Perez, Abel, Oliveira, Mafalda, Brasó-Maristany, Fara, Ibrahimi, Nusaibah, Kannan, Srinivasaraghavan, Mina, Leonardo, Herrera-Abreu, Maria Teresa, Òdena, Andreu, Sánchez-Guixé, Mònica, Capelán, Marta, Azaro, Analía, Bruna, Alejandra, Rodríguez, Olga, Guzmán, Marta, Grueso, Judit, Viaplana, Cristina, Hernández, Javier, Su, Faye, Lin, Kui, Clarke, Robert B., Caldas, Carlos, Arribas, Joaquín, Michiels, Stefan, García-Sanz, Alicia, Turner, Nicholas C., Prat, Aleix, Nuciforo, Paolo, Dienstmann, Rodrigo, Verma, Chandra Shekhar, Lopez-Bigas, Nuria, Scaltriti, Maurizio, Arnedos, Monica, Saura, Cristina, Serra, Violeta
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2023
• Subjects: Science::Biological sciences; Abemaciclib; Advanced Breast Cancer
• Online Access: https://hdl.handle.net/10356/170848
• Institution: Nanyang Technological University

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.