Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality

Journal article

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.

Authors: Gogola, E; Duarte, AA; de Ruiter, JR; Wiegant, WW; Schmid, JA

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: Cancer Cell
• Volume: 33
• Issue: 6
• Pages: 1078-1093.e12
• Publication date: 2018-06-11
• Acceptance date: 2018-05-14
• DOI: 10.1016/j.ccell.2018.05.008
• EISSN: 1878-3686
• ISSN: 1535-6108
• Pmid: 29894693
• Language: English
• Keywords: replication fork; BRCA1; PARylation; PARP inhibitor; drug resistance; PARG; PARP1; homologous recombination; BRCA2