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Unraveling the Resistance: Challenges and Advances in PARP Inhibitor Therapy for BRCA1/2 Breast Cancer

Hongjun Tang1, Jingsheng Chen1, Kangwei Jiang2

  • 1Department of Oncology, Central Hospital of Guangdong Nongken, Zhanjiang, 524002, Guangdong, China.

Anti-Cancer Agents in Medicinal Chemistry
|May 7, 2025
PubMed

Insights

This study explores how breast cancer with BRCA1/2 mutations develops resistance to PARP inhibitors (PARPi). It identifies key resistance mechanisms and suggests combination therapies to improve treatment effectiveness.

Area of Science:

  • Oncology
  • Genetics
  • Pharmacology

Background:

  • Breast cancer is a leading global cancer in women.
  • Mutations in BRCA1/2 genes elevate the risk of aggressive breast cancer.
  • PARP inhibitors (PARPi) are effective against BRCA1/2-mutated breast cancer by targeting homologous recombination (HR) repair deficiencies.

Purpose of the Study:

  • To investigate the mechanisms of acquired resistance to PARP inhibitors (PARPi) in BRCA1/2-mutated breast cancer.
  • To synthesize current clinical advancements and identify key resistance pathways.
  • To highlight strategies for overcoming PARPi resistance.

Main Methods:

  • Literature review and synthesis of recent clinical advancements.
  • Identification and analysis of molecular mechanisms driving PARPi resistance.
  • Exploration of potential therapeutic strategies to overcome resistance.

Main Results:

  • Acquired resistance to PARPi in BRCA1/2-mutated breast cancer involves multiple pathways.
  • Key resistance mechanisms include homologous recombination (HR) recovery, DNA replication fork instability, and epigenetic modifications.
  • Emerging strategies like combination therapies show promise in overcoming resistance.

Conclusions:

  • Understanding PARPi resistance mechanisms is crucial for improving treatment outcomes in BRCA1/2-mutated breast cancer.
  • Combination therapies and targeting novel pathways are potential strategies to overcome resistance.
  • Further research is needed to guide clinical practice and develop more effective treatments.
Keywords:
BRCA1BRCA2Breast cancerPARP inhibitorcombination therapiesdrug resistance.

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