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

Gogola, E
; 
Duarte, A
; 
de Ruiter, J
; 
Wiegant, W
; 
Schmid, J
; 
de Bruijn, R
; 
James, Dominic I
; 
Guerrero Llobet, S
; 
Vis, D
; 
Annunziato, S
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Abstract
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.
Authors
Gogola, E
Duarte, 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 Netherlands
Description
Date
2018-06-11
Publisher
Collections
All Paterson Institute for Cancer Research
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Type
Article
Citation
Selective loss of PARG restores PARylation and counteracts parp inhibitor-mediated synthetic lethality. 2018, 33(6): 1078-1093.e12 Cancer Cell
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Journal ISSN
Volume Title
URI
http://hdl.handle.net/10541/621110
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