| First Author | Gogola E | Year | 2018 |
| Journal | Cancer Cell | Volume | 33 |
| Issue | 6 | Pages | 1078-1093.e12 |
| PubMed ID | 29894693 | Mgi Jnum | J:262541 |
| Mgi Id | MGI:6162299 | Doi | 10.1016/j.ccell.2018.05.008 |
| Citation | Gogola E, et al. (2018) Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality. Cancer Cell 33(6):1078-1093.e12 |
| abstractText | 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. |
