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Title: | High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER<sup>+</sup> breast cancer |
Author: | Palafox Sánchez, Marta Monserrat, Laia Bellet Ezquerra, Meritxell Villacampa, Gullermo 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, Violeta |
Keywords: | Càncer de mama Resistència als medicaments Breast cancer Drug resistance |
Issue Date: | 7-Sep-2022 |
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.© 2022. The Author(s). |
Note: | Reproducció del document publicat a: https://doi.org/10.1038/s41467-022-32828-6 |
It is part of: | Nature Communications, 2022, vol. 13 |
URI: | http://hdl.handle.net/2445/197341 |
Related resource: | https://doi.org/10.1038/s41467-022-32828-6 https://doi.org/10.1038/s41467-022-34580-3 |
ISSN: | 2041-1723 |
Appears in Collections: | Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) |
Files in This Item:
File | Description | Size | Format | |
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High p16 expression and heterozygous RB1_NatureCommunications.pdf | 4.17 MB | Adobe PDF | View/Open | |
Correction_High p16 expression and heterozygous RB1 loss_NatureCommunications.pdf | Author Correction | 526.7 kB | Adobe PDF | View/Open |
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