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Combination Treatment Strategies to Overcome PARP Inhibitor Resistance

Young-Hwa Soung1, Jun Chung1

  • 1Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.

Biomolecules
|October 28, 2023
PubMed

Insights

Poly(ADP-ribose) polymerase (PARP) inhibitors offer a promising cancer therapy for HRR-deficient tumors. This review explores PARP inhibitor mechanisms, resistance, and novel combination strategies to improve patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Poly(ADP-ribose) polymerase (PARP) enzymes are crucial for DNA repair, particularly homologous recombination repair (HRR).
  • Cancers with defects in HRR pathways, such as those with BRCA1/2 mutations, are susceptible to PARP inhibitors (PARPis) via synthetic lethality.
  • PARPis represent a significant therapeutic advance for advanced ovarian and breast cancers with HRR deficiencies.

Purpose of the Study:

  • To review the molecular mechanisms underlying the therapeutic action of PARP inhibitors.
  • To summarize the known mechanisms of acquired resistance to PARP inhibitors.
  • To discuss emerging combination treatment strategies to overcome PARP inhibitor resistance.

Main Methods:

  • Literature review of studies on PARP enzyme function, DNA repair, and cancer therapeutics.
  • Analysis of molecular mechanisms of PARP inhibitor action and resistance.
  • Synthesis of current research on combination therapies involving PARPis.

Main Results:

  • PARP inhibition effectively targets cancers with HRR defects, leading to synthetic lethality.
  • Acquired resistance to PARPis is a common challenge, limiting their efficacy in some patients.
  • Emerging combination strategies show potential for enhancing PARPis' effectiveness and overcoming resistance.

Conclusions:

  • PARP inhibitors are valuable in treating HRR-deficient cancers, but resistance necessitates further research.
  • Understanding resistance mechanisms is key to developing more effective treatment regimens.
  • Combination therapies hold promise for improving clinical outcomes in patients treated with PARPis.
Keywords:
PARP inhibitorsPARP-1breast cancerscombination therapyhomologous recombination deficiencyovarian cancersresistance

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