PARP Inhibitor Resistance: A Tug-of-War in BRCA-Mutated Cells

Trends Cell Biol. 2019 Oct;29(10):820-834. doi: 10.1016/j.tcb.2019.07.008. Epub 2019 Aug 14.

Abstract

Poly-(ADP)-ribose polymerase (PARP) inhibition is synthetic lethal with deficiency for homologous recombination (HR), a pathway essential for DNA double-strand break repair. PARP inhibitors (PARPi) therefore hold great promise for the treatment of tumors with disruptive mutations in BRCA1/2 or other HR factors. Unfortunately, PARPi resistance has proved to be a major problem in the clinic. Knowledge about PARPi resistance is expanding quickly, revealing four main mechanisms that alter drug availability, affect (de)PARylation enzymes, restore HR, or restore replication fork stability. We discuss how studies on resistance mechanisms have yielded important insights into the regulation of DNA double-strand break (DSB) repair and replication fork protection, and how these studies could pave the way for novel treatment options to target resistance mechanisms or acquired vulnerabilities.

Keywords: BRCA1/2; DNA double-strand break repair; PARP inhibitor resistance; Shieldin; cancer; homologous recombination.

Publication types

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

MeSH terms

  • Animals
  • BRCA1 Protein / deficiency
  • BRCA1 Protein / genetics
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • DNA Breaks, Double-Stranded
  • DNA Repair
  • DNA, Neoplasm
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Homologous Recombination*
  • Humans
  • Mice
  • Mutation
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics*
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Tumor Cells, Cultured

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • DNA, Neoplasm
  • Poly(ADP-ribose) Polymerase Inhibitors
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1