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Molecular mechanism of PARP inhibitor resistance

Yi Huang1,2, Simin Chen1,2, Nan Yao1,2

  • 1School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, P.R. China.

Oncoscience
|September 25, 2024
PubMed

Insights

Poly (ADP-ribose) polymerases (PARP) inhibitors (PARPi) offer targeted cancer therapy by exploiting synthetic lethality in HRD-deficient cancers. This review explores mechanisms of PARPi resistance and strategies to overcome it.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Poly (ADP-ribose) polymerases (PARP) inhibitors (PARPi) represent a breakthrough in cancer therapy, leveraging synthetic lethality.
  • PARPi are effective against cancers with homologous recombination repair deficiency (HRD), such as BRCA1/2-mutant ovarian, breast, pancreatic, and prostate cancers.
  • Four PARPi (Olaparib, Rucaparib, Niraparib, Talazoparib) have been approved, significantly improving patient outcomes.

Purpose of the Study:

  • To review the molecular mechanisms underlying acquired and de novo resistance to PARP inhibitors.
  • To discuss emerging strategies for overcoming PARP inhibitor resistance in cancer treatment.

Main Methods:

  • Literature review of studies on PARP inhibitors and cancer resistance.
  • Analysis of molecular mechanisms driving resistance.
  • Synthesis of current and future therapeutic strategies.

Main Results:

  • PARPi resistance can arise through various molecular alterations, diminishing treatment efficacy.
  • Understanding these resistance mechanisms is crucial for developing effective therapeutic approaches.
  • Several strategies are being investigated to circumvent or reverse PARPi resistance.

Conclusions:

  • PARPi resistance is a significant clinical challenge that requires further investigation.
  • Developing combination therapies and novel treatment strategies is essential to overcome resistance.
  • Continued research into PARPi resistance mechanisms will guide future clinical applications and improve cancer patient survival.
Keywords:
BRCA1/2PARP inhibitorhomologous recombination (HR) repairsynthetic lethality

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