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Mechanisms of PARP inhibitor sensitivity and resistance

Alan D D'Andrea1

  • 1Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA; Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.

DNA Repair
|September 5, 2018
PubMed

Insights

Tumor cells with BRCA1/2 deficiencies are vulnerable to Poly ADP Ribose Polymerase (PARP) inhibitors. However, resistance can develop by repairing DNA damage or stabilizing replication forks, limiting treatment effectiveness.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • BRCA1/2 deficient tumors exhibit synthetic lethality with Poly ADP Ribose Polymerase (PARP) inhibitors.
  • PARP inhibitors are FDA-approved oral therapies for ovarian and breast cancers.
  • Resistance to PARP inhibitors is a significant clinical challenge.

Purpose of the Study:

  • To review the mechanisms underlying PARP inhibitor resistance in BRCA1/2-deficient tumors.
  • To provide an overview of how cancer cells overcome PARP inhibition.

Main Methods:

  • Literature review of studies on PARP inhibitor resistance.
  • Analysis of molecular mechanisms contributing to treatment failure.

Main Results:

  • Resistance can occur through restoration of homologous recombination (HR) repair pathways.
  • Stabilization of replication forks is another key mechanism of resistance.
  • Multiple pathways contribute to acquired resistance to PARP inhibitors.

Conclusions:

  • Understanding resistance mechanisms is crucial for improving PARP inhibitor efficacy.
  • Targeting resistance pathways may offer new therapeutic strategies for ovarian and breast cancer patients.
Keywords:
BRCA1/2Homologous recombinationPARP1Replication fork

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