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

Gogola, Ewa; Duarte, Alexandra A; de Ruiter, Julian R; Wiegant, Wouter W; Schmid, Jonas A; de Bruijn, Roebi; James, Dominic I; Guerrero Llobet, Sergi; Vis, Daniel J; Annunziato, Stefano; van den Broek, Bram; Barazas, Marco; Kersbergen, Ariena; van de Ven, Marieke; Tarsounas, Madalena; Ogilvie, Donald J; van Vugt, Marcel; Wessels, Lodewyk F A; Bartkova, Jirina; Gromova, Irina; ... (2018). Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality. Cancer cell, 33(6), 1078-1093.e12. Cell Press 10.1016/j.ccell.2018.05.008

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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.

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