Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality

Cancer Cell. 2018 Jun 11;33(6):1078-1093.e12. doi: 10.1016/j.ccell.2018.05.008.

Abstract

Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism. We also found the presence of PARG-negative clones in a subset of human serous ovarian and triple-negative breast cancers. PARG depletion restores PAR formation and partially rescues PARP1 signaling. Importantly, PARG inactivation exposes vulnerabilities that can be exploited therapeutically.

Keywords: BRCA1; BRCA2; PARG; PARP inhibitor; PARP1; PARylation; drug resistance; homologous recombination; replication fork.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Female
  • Glycoside Hydrolases / antagonists & inhibitors
  • Glycoside Hydrolases / genetics*
  • Glycoside Hydrolases / metabolism
  • Homologous Recombination / drug effects
  • Homologous Recombination / genetics
  • Humans
  • Mice, 129 Strain
  • Mice, Knockout
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
  • Poly (ADP-Ribose) Polymerase-1 / genetics*
  • Poly (ADP-Ribose) Polymerase-1 / metabolism
  • Poly ADP Ribosylation / drug effects
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Synthetic Lethal Mutations*

Substances

  • BRCA1 Protein
  • Poly(ADP-ribose) Polymerase Inhibitors
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Glycoside Hydrolases
  • poly ADP-ribose glycohydrolase