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dc.contributor.authorGogola, E
dc.contributor.authorDuarte, A
dc.contributor.authorde Ruiter, J
dc.contributor.authorWiegant, W
dc.contributor.authorSchmid, J
dc.contributor.authorde Bruijn, R
dc.contributor.authorJames, Dominic I
dc.contributor.authorGuerrero Llobet, S
dc.contributor.authorVis, D
dc.contributor.authorAnnunziato, S
dc.contributor.authorvan den Broek, B
dc.contributor.authorBarazas, M
dc.contributor.authorKersbergen, A
dc.contributor.authorvan de Ven, M
dc.contributor.authorTarsounas, M
dc.contributor.authorOgilvie, D
dc.contributor.authorvan Vugt, M
dc.contributor.authorWessels, L
dc.contributor.authorBartkova, J
dc.contributor.authorGromova, I
dc.contributor.authorAndújar-Sánchez, M
dc.contributor.authorBartek, J
dc.contributor.authorLopes, M
dc.contributor.authorvan Attikum, H
dc.contributor.authorBorst, P
dc.contributor.authorJonkers, J
dc.contributor.authorRottenberg, S
dc.date.accessioned2018-07-15T15:05:41Z
dc.date.available2018-07-15T15:05:41Z
dc.date.issued2018-06-11
dc.identifier.citationSelective loss of PARG restores PARylation and counteracts parp inhibitor-mediated synthetic lethality. 2018, 33(6): 1078-1093.e12 Cancer Cellen
dc.identifier.issn1878-3686
dc.identifier.pmid29894693
dc.identifier.doi10.1016/j.ccell.2018.05.008
dc.identifier.urihttp://hdl.handle.net/10541/621110
dc.description.abstractInhibitors 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.
dc.language.isoenen
dc.rightsArchived with thanks to Cancer cellen
dc.titleSelective loss of PARG restores PARylation and counteracts parp inhibitor-mediated synthetic lethality.en
dc.typeArticleen
dc.contributor.departmentDivision of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlandsen
dc.identifier.journalCancer Cellen
html.description.abstractInhibitors 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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