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

Ángel Guerrero-Zotano1,2, Stefania Belli3, Christoph Zielinski4,5

  • 1Medical Oncology, Instituto Valenciano de Oncología, Valencia, Spain.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|February 7, 2023
PubMed
Abstract

Insights

Non-luminal breast cancer and high CCNE1 predict poor response to CDK4/6 inhibitors. High PLK1 levels indicate resistance, but PLK1 inhibition may reverse it in hormone receptor-positive metastatic breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC) requires identification of patients resistant to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i).
  • Discovering therapeutic targets to overcome CDK4/6i resistance is crucial for improving patient outcomes.

Purpose of the Study:

  • To validate non-luminal breast cancer subtype and CCNE1 as biomarkers for poor response to CDK4/6 inhibitors plus endocrine therapy (ET).
  • To identify novel therapeutic targets for reversing resistance to CDK4/6i in HR+/HER2- MBC.

Main Methods:

  • mRNA gene expression profiling and progression-free survival (PFS) correlation in 455 HR+/HER2- MBC patients from the PEARL study (palbociclib+ET vs. capecitabine).
  • Generation and characterization of endocrine therapy-resistant ER+/HER2- breast cancer cell lines.
  • Analysis of Polo-like kinase 1 (PLK1) expression in patient samples and cell line models.

Main Results:

  • Non-luminal tumors were more prevalent in metastatic samples and associated with significantly worse PFS with palbociclib+ET compared to capecitabine (HR 4.16, P < 0.0001).
  • High CCNE1 expression correlated with worse PFS on palbociclib+ET (HR 1.55, P = 0.0036).
  • Patients refractory to palbociclib+ET exhibited higher PLK1 mRNA levels, which were also associated with worse PFS in an independent dataset (PALOMA3). PLK1 inhibition reversed resistance in cell line models.

Conclusions:

  • Non-luminal subtype and high CCNE1 are confirmed biomarkers for resistance to CDK4/6i+ET in HR+ MBC.
  • Elevated PLK1 mRNA levels identify patients with poor response to palbociclib, suggesting PLK1 as a potential therapeutic target to overcome resistance.

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