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Overcoming Resistance to CDK4/6 inhibitors in Hormone Receptor positive, HER2 negative breast cancer: Innovative

Federica Giugliano1, Carmine De Angelis2, Barbara Pistilli3

  • 1INSERM U981, Gustave Roussy, Villejuif, France; Department of Medical Oncology, Gustave Roussy, Villejuif, France; Department of Oncology and Hematology-Oncology, University of Milano, Milan, Italy.

Cancer Treatment Reviews
|June 22, 2025
PubMed

Insights

Cyclin-dependent kinase 4/6 inhibitors combined with endocrine therapy benefit many breast cancer patients. This review explores resistance mechanisms and highlights strategies for developing more effective combination therapies.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Hormone receptor-positive, HER2-negative breast cancer (HR+/HER2-) is a major health concern.
  • Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) are standard treatments for HR+/HER2- breast cancer.
  • Intrinsic and acquired resistance to CDK4/6i + ET limit treatment efficacy in a significant patient subset.

Purpose of the Study:

  • To review the mechanisms of action and resistance to CDK4/6 inhibitors in breast cancer.
  • To provide an overview of emerging efficacy, safety, and biomarker-driven strategies for CDK4/6i combinations.
  • To identify key research priorities for developing novel therapeutic combinations.

Main Methods:

  • Comprehensive literature review of preclinical and clinical studies on CDK4/6 inhibitors.
  • Analysis of biomarker data from patients treated with CDK4/6i plus ET.
  • Synthesis of current evidence on resistance mechanisms and combination strategies.

Main Results:

  • CDK4/6i + ET demonstrate significant clinical benefit in HR+/HER2- breast cancer.
  • Intrinsic resistance occurs in ~20% of tumors; acquired resistance develops over time.
  • Biomarker analyses reveal potential targets for overcoming resistance.

Conclusions:

  • Understanding resistance mechanisms is crucial for improving CDK4/6i efficacy.
  • Biomarker-driven strategies and novel combinations are essential for overcoming resistance.
  • Further research is needed to guide the development of next-generation therapies.
Keywords:
CDK4/6 inhibitorsCombinationMetastatic breast cancerResistance

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