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

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. H...

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Autores: Palafox, Marta|||0000-0002-1762-3250, Monserrat, Laia|||0000-0002-8802-3033, Bellet Ezquerra, Meritxell|||0000-0001-8859-8307, Villacampa Javierre, Guillermo|||0000-0003-4868-6585, Gonzalez-Perez, Abel|||0000-0002-8582-4660, Oliveira, Mafalda|||0000-0001-9152-8799, Brasó-Maristany, Fara|||0000-0001-5440-9643, Ibrahimi, Nusaibah|||0000-0003-4537-0323, Kannan, Srinivasaraghavan|||0000-0002-9539-5249, Mina, Leonardo, Herrera-Abreu, Maria Teresa, Òdena, Andreu|||0000-0003-1529-880X, Sánchez Guixé, Mònica|||0000-0002-9430-4413, Capelán, Marta, Azaro, Analía, Bruna, Alejandra|||0000-0003-1214-9665, Rodríguez, Olga|||0000-0002-0123-9975, Guzmán, Marta|||0000-0002-0924-9887, Grueso, Judit|||0000-0003-1093-7940, Viaplana, Cristina|||0000-0001-8904-4330, Hernandez-Losa, Javier|||0000-0003-1526-3201, Su, Faye, Lin, Kui, Clarke, Robert B.|||0000-0001-5407-3123, Caldas, Carlos|||0000-0003-3547-1489, Arribas, Joaquín V.|||0000-0002-0504-0664, Michiels, Stefan|||0000-0002-6963-2968, García-Sanz, Alicia, Turner, Nicholas C.|||0000-0001-8937-0873, Prat, Aleix|||0000-0003-2377-540X, Nuciforo, Paolo|||0000-0003-1380-0990, Dienstmann, Rodrigo|||0000-0001-5997-318X, Verma, Chandra S., Lopez-Bigas, Nuria|||0000-0003-4925-8988, Scaltriti, Maurizio|||0000-0002-5522-1447, Arnedos, Monica, Saura Manich, Cristina|||0000-0001-8296-5065, Serra, Violeta|||0000-0001-6620-1065
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:281817
Acceso en línea:https://ddd.uab.cat/record/281817
https://dx.doi.org/urn:doi:10.1038/s41467-022-32828-6
Access Level:acceso abierto
Palabra clave:Breast cancer
Cancer models
Predictive markers
Descripción
Sumario: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. CDK4/6 inhibitor resistance is common in breast cancer. Here, the authors show that p16 overexpression may be linked to reduced efficacy of CDK4/6 inhibition, and show that the combination with PI3K inhibitors may increase anti-tumour effects.

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