Selective loss of PARG restores PARylation and counteracts parp inhibitor-mediated synthetic lethality.
Authors
Gogola, EDuarte, A
de Ruiter, J
Wiegant, W
Schmid, J
de Bruijn, R
James, Dominic I
Guerrero Llobet, S
Vis, D
Annunziato, S
van den Broek, B
Barazas, M
Kersbergen, A
van de Ven, M
Tarsounas, M
Ogilvie, D
van Vugt, M
Wessels, L
Bartkova, J
Gromova, I
Andújar-Sánchez, M
Bartek, J
Lopes, M
van Attikum, H
Borst, P
Jonkers, J
Rottenberg, S
Affiliation
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam 1066CX, the NetherlandsIssue Date
2018-06-11
Metadata
Show full item recordAbstract
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.Citation
Selective loss of PARG restores PARylation and counteracts parp inhibitor-mediated synthetic lethality. 2018, 33(6): 1078-1093.e12 Cancer CellJournal
Cancer CellDOI
10.1016/j.ccell.2018.05.008PubMed ID
29894693Type
ArticleLanguage
enISSN
1878-3686ae974a485f413a2113503eed53cd6c53
10.1016/j.ccell.2018.05.008