CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2−Metastatic Breast Cancer

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 hig...

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Detalles Bibliográficos
Autores: 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, Margelí 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
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/202133
Acceso en línea:https://hdl.handle.net/2445/202133
Access Level:acceso abierto
Palabra clave:Càncer de mama
Receptors d'hormones
Oncogens
Breast cancer
Hormone receptors
Oncogenes
Descripción
Sumario: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.

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