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Title: | CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2−Metastatic Breast Cancer |
Author: | Guerrero Zotano, Ángel Belli, Stefania Zielinski, Christoph Gil Gil, Miguel Fernández Serra, Antonio Ruíz Borrego, Manuel Ciruelos, Eva Pascual, Javier Muñoz Mateu, Montserrat Bermejo, Begoña Margeli Vila, Mireia Antón, Antonio Murillo, Laura Nissenbaum, Bella Liu, Yuan Herranz, Jesús Fernández García, Daniel Caballero, Rosalía López Guerrero, José Antonio Bianco, Roberto Formisano, Luigi Turner, Nicholas Martín, Miguel |
Keywords: | Càncer de mama Receptors d'hormones Oncogens Breast cancer Hormone receptors Oncogenes |
Issue Date: | 14-Apr-2023 |
Publisher: | American Association for Cancer Research (AACR) |
Abstract: | Purpose: In hormone receptor???positive (HR+)/HER2- meta-static breast cancer (MBC), it is imperative to identify patients who respond poorly to cyclin-dependent kinase 4/6 inhibitors (CDK4/ 6i) and to discover therapeutic targets to reverse this resistance. Non-luminal breast cancer subtype and high levels of CCNE1 are candidate biomarkers in this setting, but further validation is needed. Experimental Design: We performed mRNA gene expression profiling and correlation with progression-free survival (PFS) on 455 tumor samples included in the phase III PEARL study, which assigned patients with HR+/HER2-MBC to receive palbociclib+endocrine therapy (ET) versus capecitabine. Estrogen receptor???positive (ER+)/ HER2-breast cancer cell lines were used to generate and characterize resistance to palbociclib+ET. Results: Non-luminal subtype was more prevalent in meta-static (14%) than in primary tumor samples (4%). Patients with??non-luminal tumors had median PFS of 2.4 months with palbociclib+ET and 9.3 months with capecitabine; HR 4.16, adjusted P value < 0.0001. Tumors with high CCNE1 expression (above median) also had worse median PFS with palbociclib+ET (6.2 months) than with capecitabine (9.3 months); HR 1.55, adjusted P value = 0.0036. In patients refractory to palbociclib+ET (PFS in the lower quartile), we found higher levels of Polo-like kinase 1 (PLK1). In an independent data set (PALOMA3), tumors with high PLK1 show worse median PFS than those with low PLK1 expression under palbociclib+ET treatment. In ER+/HER2-cell line models, we show that PLK1 inhibition reverses resistance to palbociclib+ET. Conclusions: We confirm the association of non-luminal sub-type and CCNE1 with resistance to CDK4/6i+ET in HR+ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i. |
Note: | Reproducció del document publicat a: https://doi.org/10.1158/1078-0432.CCR-22-2206 |
It is part of: | Clinical Cancer Research, 2023, vol. 29, num. 8, p. 1557-1568 |
URI: | http://hdl.handle.net/2445/202133 |
Related resource: | https://doi.org/10.1158/1078-0432.CCR-22-2206 |
ISSN: | 1557-3265 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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