American Association for Cancer Research
ccr-22-2206_supplementary_figure_s10_suppfs10.docx (412.67 kB)

Supplementary Figure S10 from CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2− Metastatic Breast Cancer

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posted on 2023-04-01, 00:22 authored by Ángel Guerrero-Zotano, Stefania Belli, Christoph Zielinski, Miguel Gil-Gil, Antonio Fernandez-Serra, Manuel Ruiz-Borrego, Eva Maria Ciruelos Gil, Javier Pascual, Montserrat Muñoz-Mateu, Begoña Bermejo, Mireia Margeli Vila, Antonio Antón, Laura Murillo, Bella Nissenbaum, Yuan Liu, Jesús Herranz, Daniel Fernández-García, Rosalía Caballero, José Antonio López-Guerrero, Roberto Bianco, Luigi Formisano, Nicholas Turner, Miguel Martín

Evaluation of volasertib effects on tumor spheroid growth and on the activation of signal transduction pathways in PalboR and FPR cells



In hormone receptor–positive (HR+)/HER2− metastatic 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. 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. Non-luminal subtype was more prevalent in metastatic (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. We confirm the association of non-luminal subtype 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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