High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER<sup>+</sup> 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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Detalhes bibliográficos
Autores: Palafox Sánchez, Marta, Monserrat Vicente, Laia, Bellet Ezquerra, Meritxell, Villacampa, Guillermo, González Pérez, Abel, Oliveira, Mafalda, Brasó-Maristany, Fara, Ibrahimi, Nusaibah, Kannan, Srinivasaraghavan, Mina, Leonardo, Herrera Abreu, Maria Teresa, Odena, Andreu, Sánchez Guixé, Mònica, Capelán, Marta, Azaro, Analía, Bruna, Alejandra, Rodriguez, Olga, Guzmán, Marta, Grueso, Judit, Viaplana, Cristina, Hernandez, Javier, Su, Faye, Lin, Kui, Clarke, Robert, Caldas, Carlos, Arribas, Joaquín, Michiels, Stefan, García Sanz, Alicia, Turner, Nicholas, 1951-, Prat Aparicio, Aleix, Nuciforo, Paolo, Dienstmann, Rodrigo, Verma, Chandra S, López Bigas, Núria, Scaltriti, Maurizio, Arnedos, Monica, Saura, Cristina, Serra Elizalde, Violeta
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/197341
Acesso em linha:https://hdl.handle.net/2445/197341
Access Level:acceso abierto
Palavra-chave:Càncer de mama
Resistència als medicaments
Breast cancer
Drug resistance
Descrição
Resumo: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.© 2022. The Author(s).

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