Mechanisms of PARP-Inhibitor-Resistance in BRCA-Mutated Breast Cancer and New Therapeutic Approaches

Sayra Dilmac, Bulent Ozpolat

Research output: Contribution to journalReview articlepeer-review

6 Scopus citations


The recent success of Poly (ADP-ribose) polymerase (PARP) inhibitors has led to the approval of four different PARP inhibitors for the treatment of BRCA1/2-mutant breast and ovarian cancers. About 40–50% of BRCA1/2-mutated patients do not respond to PARP inhibitors due to a preexisting innate or intrinsic resistance; the majority of patients who initially respond to the therapy inevitably develop acquired resistance. However, subsets of patients experience a long-term response (>2 years) to treatment with PARP inhibitors. Poly (ADP-ribose) polymerase 1 (PARP1) is an enzyme that plays an important role in the recognition and repair of DNA damage. PARP inhibitors induce “synthetic lethality” in patients with tumors with a homologous-recombination-deficiency (HRD). Several molecular mechanisms have been identified as causing PARP-inhibitor-resistance. In this review, we focus on the molecular mechanisms underlying the PARP-inhibitor-resistance in BRCA-mutated breast cancer and summarize potential therapeutic strategies to overcome the resistance mechanisms.

Original languageEnglish (US)
Article number3642
Issue number14
StatePublished - Jul 16 2023


  • BRCA1
  • BRCA2
  • PARP
  • PARPi
  • PARPi-resistance
  • breast cancer
  • combination therapies

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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