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Shaping CDK4/6 Inhibitor Resistance: BRCA2 Germline Alterations Bias toward RB1 Inactivation

Fabiana Napolitano1, Ariella B Hanker2

  • 1Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.

Cancer Research
|April 29, 2026
PubMed

Insights

Germline BRCA2 alterations in breast cancer can lead to RB1 alterations, causing resistance to CDK4/6 inhibitors. These tumors may benefit more from PARP inhibitors, offering new treatment strategies.

Area of Science:

  • Oncology
  • Genetics
  • Genomics

Background:

  • CDK4/6 inhibitors (CDK4/6i) are crucial for metastatic hormone receptor-positive (HR+) breast cancer, but resistance limits survival.
  • Mechanisms of CDK4/6i resistance are diverse and unpredictable, posing a clinical challenge.

Purpose of the Study:

  • To investigate the link between germline BRCA2 (gBRCA2) alterations and resistance to CDK4/6i in HR+ breast cancer.
  • To identify RB1 alterations as a mechanism of resistance and explore alternative therapeutic strategies.

Main Methods:

  • Large-scale clinical genomics analysis of HR+ breast cancer patients.
  • Investigation of the relationship between gBRCA2 status, RB1 alterations, and response to CDK4/6i and PARP inhibitors (PARPi).
  • Mechanistic studies to elucidate the role of chromosome 13q deletions and homologous recombination deficiency (HRD).

Main Results:

  • gBRCA2-altered tumors show enrichment for RB1 alterations and reduced benefit from CDK4/6i.
  • RB1 hemizygosity, due to the shared 13q locus with BRCA2, is a key mechanism of resistance.
  • HRD-associated mutagenesis facilitates the acquisition of a second RB1 inactivating hit.
  • Baseline RB1 hemizygosity predicts poor outcomes with CDK4/6i, independent of germline status.
  • gBRCA2-altered tumors retain sensitivity to PARP inhibition.

Conclusions:

  • Germline BRCA2 alterations predispose tumors to RB1 loss-of-function, driving CDK4/6i resistance in HR+ breast cancer.
  • RB1 hemizygosity serves as a predictive biomarker for CDK4/6i response.
  • Findings support strategic sequencing of PARPi and CDK4/6i in gBRCA2-mutated patients and offer insights for intercepting resistance.

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