CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2- Metastatic Breast Cancer.
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Date
2023-04-14Author
Guerrero-Zotano, Á
Belli, S
Zielinski, C
Gil-Gil, M
Fernandez-Serra, A
Ruiz-Borrego, M
Ciruelos Gil, EM
Pascual, J
Muñoz-Mateu, M
Bermejo, B
Margeli Vila, M
Antón, A
Murillo, L
Nissenbaum, B
Liu, Y
Herranz, J
Fernández-García, D
Caballero, R
López-Guerrero, JA
Bianco, R
Formisano, L
Turner, N
Martín, M
Type
Journal Article
Metadata
Show full item recordAbstract
PURPOSE: 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. 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 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. CONCLUSIONS: 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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Subject
Humans
Female
Breast Neoplasms
Capecitabine
Receptor, ErbB-2
Antineoplastic Combined Chemotherapy Protocols
Proto-Oncogene Proteins
Cyclin-Dependent Kinase 4
RNA, Messenger
Oncogene Proteins
Cyclin E
Research team
Molecular Oncology
Language
eng
Date accepted
2023-02-02
License start date
2023-04-14
Citation
Clinical Cancer Research, 2023, 29 (8), pp. 1557 - 1568
Publisher
AMER ASSOC CANCER RESEARCH