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

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 effec...

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Bibliographic Details
Main Authors: Gogola, E, Duarte, AA, de Ruiter, JR, Wiegant, WW, Schmid, JA, de Bruijn, R, James, DI, Llobet, SG, 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
Format: Journal article
Language:English
Published: Cell Press 2018
Description
Summary: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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