DNA Replication Vulnerabilities Render Ovarian Cancer Cells Sensitive to Poly(ADP-Ribose) Glycohydrolase Inhibitors

Cancer Cell. 2019 Mar 18;35(3):519-533.e8. doi: 10.1016/j.ccell.2019.02.004.


Inhibitors of poly(ADP-ribose) polymerase (PARP) have demonstrated efficacy in women with BRCA-mutant ovarian cancer. However, only 15%-20% of ovarian cancers harbor BRCA mutations, therefore additional therapies are required. Here, we show that a subset of ovarian cancer cell lines and ex vivo models derived from patient biopsies are sensitive to a poly(ADP-ribose) glycohydrolase (PARG) inhibitor. Sensitivity is due to underlying DNA replication vulnerabilities that cause persistent fork stalling and replication catastrophe. PARG inhibition is synthetic lethal with inhibition of DNA replication factors, allowing additional models to be sensitized by CHK1 inhibitors. Because PARG and PARP inhibitor sensitivity are mutually exclusive, our observations demonstrate that PARG inhibitors have therapeutic potential to complement PARP inhibitor strategies in the treatment of ovarian cancer.

Keywords: DNA damage; HGSOC; PARG; PARP; TIMELESS; replication catastrophe; γH2AX.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Checkpoint Kinase 1
  • DNA Replication / drug effects*
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Glycoside Hydrolases / antagonists & inhibitors
  • Humans
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / genetics*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Quinazolinones / pharmacology


  • Enzyme Inhibitors
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Quinazolinones
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Glycoside Hydrolases
  • poly ADP-ribose glycohydrolase