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 Gonzalez-Perez, Mafalda Oliveira, Fara Brasó-Maristany, Nusaibah Ibrahimi, Srinivasaraghavan Kannan, Leonardo Mina, Maria Teresa Herrera-Abreu, Andreu Òdena, Mònica Sánchez-Guixé, Marta Capelán, Analía Azaro, Alejandra Bruna, Olga Rodríguez, Marta Guzmán, Judit Grueso, Cristina Viaplana, Javier Hernández, Faye Su, Kui Lin, Robert B. Clarke, Carlos Caldas, Joaquín Arribas, Stefan Michiels, Alicia García-Sanz, Nicholas C. Turner, Aleix Prat, Paolo Nuciforo, Rodrigo Dienstmann, Chandra S. Verma, Nuria Lopez-Bigas, Maurizio Scaltriti, Monica Arnedos, Cristina Saura and Violeta Serra ()
Additional contact information
Marta Palafox: Vall d’Hebron Institute of Oncology
Laia Monserrat: Vall d’Hebron Institute of Oncology
Meritxell Bellet: Vall d’Hebron Institute of Oncology
Guillermo Villacampa: Vall d’Hebron Institute of Oncology
Abel Gonzalez-Perez: Institute for Research in Biomedicine (IRB Barcelona)
Mafalda Oliveira: Vall d’Hebron Institute of Oncology
Fara Brasó-Maristany: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
Nusaibah Ibrahimi: Service de Biostatistique et d’Epidémiologie, Gustave Roussy
Srinivasaraghavan Kannan: Bioinformatics Institute (A*STAR)
Leonardo Mina: Medica Scientia Innovation Research (MedSIR)
Maria Teresa Herrera-Abreu: The Breast Cancer Now Research Centre
Andreu Òdena: Vall d’Hebron Institute of Oncology
Mònica Sánchez-Guixé: Vall d’Hebron Institute of Oncology
Marta Capelán: Vall d’Hebron Institute of Oncology
Analía Azaro: Vall d’Hebron Institute of Oncology
Alejandra Bruna: The Institute of Cancer Research
Olga Rodríguez: Vall d’Hebron Institute of Oncology
Marta Guzmán: Vall d’Hebron Institute of Oncology
Judit Grueso: Vall d’Hebron Institute of Oncology
Cristina Viaplana: Vall d’Hebron Institute of Oncology
Javier Hernández: Vall d’Hebron Institute of Research (VHIR)
Faye Su: Novartis Pharmaceuticals
Kui Lin: Genentech, Inc., South San Francisco
Robert B. Clarke: Breast Biology Group, Manchester Breast Centre
Carlos Caldas: Cancer Research UK
Joaquín Arribas: CIBERONC, Vall d’Hebron Institute of Oncology
Stefan Michiels: Service de Biostatistique et d’Epidémiologie, Gustave Roussy
Alicia García-Sanz: Medica Scientia Innovation Research (MedSIR)
Nicholas C. Turner: The Breast Cancer Now Research Centre
Aleix Prat: August Pi i Sunyer Biomedical Research Institute (IDIBAPS)
Paolo Nuciforo: Vall d’Hebron Institute of Oncology
Rodrigo Dienstmann: Vall d’Hebron Institute of Oncology
Chandra S. Verma: Bioinformatics Institute (A*STAR)
Nuria Lopez-Bigas: Institute for Research in Biomedicine (IRB Barcelona)
Maurizio Scaltriti: Memorial Sloan-Kettering Cancer Center
Monica Arnedos: Gustave Roussy
Cristina Saura: Vall d’Hebron Institute of Oncology
Violeta Serra: Vall d’Hebron Institute of Oncology

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32828-6

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