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

Ewa Gogola1, Alexandra A Duarte1, Julian R de Ruiter2

  • 1Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, Amsterdam 1066CX, the Netherlands.

Cancer Cell
|June 13, 2018
PubMed

Insights

Loss of PAR glycohydrolase (PARG) confers resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) in homologous recombination-deficient cancers. PARG inactivation reveals new therapeutic vulnerabilities in ovarian and breast cancers.

Area of Science:

  • Oncology
  • Cancer Biology
  • Genetics

Background:

  • Poly(ADP-ribose) polymerase inhibitors (PARPi) are effective against homologous recombination (HR)-deficient cancers.
  • Drug resistance to PARPi is a significant clinical challenge.
  • Mechanisms of PARPi resistance independent of HR restoration are poorly understood.

Purpose of the Study:

  • To identify novel mechanisms of PARPi resistance in HR-deficient cancers.
  • To investigate the role of PAR glycohydrolase (PARG) in PARPi resistance.
  • To explore therapeutic vulnerabilities associated with PARG inactivation.

Main Methods:

  • Genetic screens in Brca2-mutated mouse mammary tumors.
  • Multi-omics analysis of PARPi-sensitive and -resistant tumors.
  • Analysis of human serous ovarian and triple-negative breast cancer samples.

Main Results:

  • Loss of PAR glycohydrolase (PARG) was identified as a major PARPi resistance mechanism.
  • PARG-negative clones were found in human ovarian and breast cancers.
  • PARG depletion partially restored poly(ADP-ribose) (PAR) formation and PARP1 signaling.

Conclusions:

  • PARG inactivation is a key driver of PARPi resistance in HR-deficient cancers.
  • PARG-negative cancer cells exhibit vulnerabilities exploitable for therapy.
  • Targeting PARG may offer new therapeutic strategies for resistant cancers.
Keywords:
BRCA1BRCA2PARGPARP inhibitorPARP1PARylationdrug resistancehomologous recombinationreplication fork

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