Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication




Journal article


Cancer Cell

Publication Date





1078 - 1093.e12


BRCA1, BRCA2, PARG, PARP inhibitor, PARP1, PARylation, drug resistance, homologous recombination, replication fork, Animals, BRCA1 Protein, Breast Neoplasms, Cell Line, Tumor, Female, Glycoside Hydrolases, Homologous Recombination, Humans, Mice, 129 Strain, Mice, Knockout, Ovarian Neoplasms, Poly (ADP-Ribose) Polymerase-1, Poly ADP Ribosylation, Poly(ADP-ribose) Polymerase Inhibitors, Synthetic Lethal Mutations