Mechanisms of PARP inhibitor sensitivity and resistance

DNA Repair (Amst). 2018 Nov:71:172-176. doi: 10.1016/j.dnarep.2018.08.021. Epub 2018 Aug 23.

Abstract

BRCA1 and BRCA2 deficient tumor cells are sensitive to inhibitors of Poly ADP Ribose Polymerase (PARP1) through the mechanism of synthetic lethality. Several PARP inhibitors, which are oral drugs and generally well tolerated, have now received FDA approval for various ovarian cancer and breast cancer indications. Despite their use in the clinic, PARP inhibitor resistance is common and develops through multiple mechanisms. Broadly speaking, BRCA1/2-deficient tumor cells can become resistant to PARP inhibitors by restoring homologous recombination (HR) repair and/or by stabilizing their replication forks. Here, we review the mechanism of PARP inhibitor resistance.

Keywords: BRCA1/2; Homologous recombination; PARP1; Replication fork.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • BRCA1 Protein
  • BRCA2 Protein
  • Drug Resistance, Neoplasm*
  • Female
  • Homologous Recombination
  • Humans
  • Male
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / physiopathology
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use

Substances

  • Antineoplastic Agents
  • BRCA1 Protein
  • BRCA2 Protein
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly (ADP-Ribose) Polymerase-1