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.