Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality
Copyright policy )Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality
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.
- University of Bern Switzerland
- University of Zurich Switzerland
- University Medical Center Groningen Netherlands
- University of Manchester United Kingdom
- University of Manchester United Kingdom
Mice, 129 Strain, Glycoside Hydrolases, DEFICIENT CELLS, MAMMARY-TUMORS, Poly (ADP-Ribose) Polymerase-1, homologous recombination, Breast Neoplasms, POLY(ADP-RIBOSE) POLYMERASE, Poly(ADP-ribose) Polymerase Inhibitors, PARP1, HOMOLOGOUS RECOMBINATION, Poly ADP Ribosylation, Cell Line, Tumor, BREAST-CANCER, PARG, Animals, Humans, REPLICATION FORK REVERSAL, Homologous Recombination, REPAIR, Mice, Knockout, Ovarian Neoplasms, drug resistance, Manchester Cancer Research Centre, BRCA1 Protein, CONDITIONAL MOUSE MODEL, BRCA1, BRCA2, ResearchInstitutes_Networks_Beacons/mcrc; name=Manchester Cancer Research Centre, PARylation, COMBINATION THERAPY, PARP inhibitor, DNA-DAMAGE-RESPONSE, replication fork, Female, Synthetic Lethal Mutations
Mice, 129 Strain, Glycoside Hydrolases, DEFICIENT CELLS, MAMMARY-TUMORS, Poly (ADP-Ribose) Polymerase-1, homologous recombination, Breast Neoplasms, POLY(ADP-RIBOSE) POLYMERASE, Poly(ADP-ribose) Polymerase Inhibitors, PARP1, HOMOLOGOUS RECOMBINATION, Poly ADP Ribosylation, Cell Line, Tumor, BREAST-CANCER, PARG, Animals, Humans, REPLICATION FORK REVERSAL, Homologous Recombination, REPAIR, Mice, Knockout, Ovarian Neoplasms, drug resistance, Manchester Cancer Research Centre, BRCA1 Protein, CONDITIONAL MOUSE MODEL, BRCA1, BRCA2, ResearchInstitutes_Networks_Beacons/mcrc; name=Manchester Cancer Research Centre, PARylation, COMBINATION THERAPY, PARP inhibitor, DNA-DAMAGE-RESPONSE, replication fork, Female, Synthetic Lethal Mutations
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