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Poly-ADP-ribosyl-polymerase inhibitor resistance mechanisms and their therapeutic implications

Kelly E McCann1

  • 1David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA.

Current Opinion in Obstetrics & Gynecology
|December 13, 2018
PubMed
Abstract

Insights

Poly(ADP-ribose) polymerase (PARP) inhibitors are vital for ovarian cancer, but resistance develops. Understanding resistance mechanisms like DNA repair pathway restoration is key to improving PARP inhibitor efficacy.

Area of Science:

  • Oncology
  • Genetics
  • Pharmacology

Background:

  • High-grade serous ovarian carcinoma (HGSOC) treatment increasingly involves Poly(ADP-ribose) polymerase (PARP) inhibitors.
  • PARP inhibitors are particularly effective in BRCA1/2-mutated cancers and as maintenance therapy for platinum-sensitive HGSOC due to homologous recombination DNA repair defects.

Purpose of the Study:

  • To review the current understanding of Poly(ADP-ribose) polymerase (PARP) inhibitor resistance mechanisms in ovarian cancer.
  • To inform the development of rational combination strategies to overcome or prevent PARP inhibitor resistance.

Main Methods:

  • Literature review of studies on PARP inhibitors in ovarian cancer.
  • Analysis of identified mechanisms of tumor resistance to PARP inhibitor monotherapy.

Main Results:

  • Tumor resistance to PARP inhibitor monotherapy is an inevitable challenge in ovarian cancer treatment.
  • Key resistance mechanisms include restoration of homologous recombination repair (HRR) proficiency, reduced cellular dependence on PARP, and activation of pro-growth signaling pathways.

Conclusions:

  • Elucidating PARP inhibitor resistance mechanisms is crucial for designing effective combination therapies.
  • Future strategies should aim to extend therapeutic benefits and abrogate resistance in ovarian cancer patients treated with PARP inhibitors.

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