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

Gogola E., Duarte AA., de Ruiter JR., Wiegant WW., Schmid JA., de Bruijn R., James DI., Guerrero Llobet S., Vis DJ., Annunziato S., van den Broek B., Barazas M., Kersbergen A., van de Ven M., Tarsounas M., Ogilvie DJ., van Vugt M., Wessels LFA., Bartkova J., Gromova I., Andújar-Sánchez M., Bartek J., Lopes M., van Attikum H., Borst P., Jonkers J., Rottenberg S.

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.

DOI

10.1016/j.ccell.2018.05.008

Type

Journal article

Journal

Cancer Cell

Publication Date

11/06/2018

Volume

33

Pages

1078 - 1093.e12

Keywords

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

Permalink Original publication