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Insights into the Possible Molecular Mechanisms of Resistance to PARP Inhibitors

Claudia Piombino1, Laura Cortesi1

  • 1Genetic Oncology Unit, Department of Oncology and Haematology, University Hospital of Modena, 41125 Modena, Italy.

Cancers
|June 10, 2022
PubMed

Insights

PARP inhibitors are crucial for treating BRCA1/2-mutated cancers, but resistance is a growing concern. This review explores molecular mechanisms driving resistance to PARP inhibitors in these cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Poly (ADP-ribose) polymerase 1 (PARP1) is vital for DNA damage response.
  • PARP inhibitors are effective in BRCA1/2-mutated cancers via synthetic lethality.
  • Therapeutic resistance to PARP inhibitors is an emerging clinical challenge.

Purpose of the Study:

  • To review molecular mechanisms underlying primary and secondary resistance to PARP inhibitors.
  • To analyze interactions between PARP1, DNA repair, and signaling pathways in BRCA1/2-mutated cancers.

Main Methods:

  • Literature review of molecular findings on PARP inhibitor resistance.
  • Analysis of interactions between PARP1, cell cycle, PI3K/AKT signaling, and DNA repair pathways.

Main Results:

  • Several resistance mechanisms have been proposed, with secondary BRCA1/2 mutations being clinically validated.
  • Understanding complex interactions is key to elucidating resistance development.

Conclusions:

  • Elucidating resistance mechanisms is critical for improving PARP inhibitor efficacy in BRCA1/2-mutated cancers.
  • Further research into interconnected pathways is needed to overcome resistance.
Keywords:
BRCA1BRCA2PARP inhibitorsfork stabilizationhomologous recombinationnon-homologous end joining

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