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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Published in:Cancer cell Vol. 33; no. 6; p. 1078
Main Authors: Gogola, Ewa, Duarte, Alexandra A, de Ruiter, Julian R, Wiegant, Wouter W, Schmid, Jonas A, de Bruijn, Roebi, James, Dominic I, Guerrero Llobet, Sergi, Vis, Daniel J, Annunziato, Stefano, van den Broek, Bram, Barazas, Marco, Kersbergen, Ariena, van de Ven, Marieke, Tarsounas, Madalena, Ogilvie, Donald J, van Vugt, Marcel, Wessels, Lodewyk F A, Bartkova, Jirina, Gromova, Irina, Andújar-Sánchez, Miguel, Bartek, Jiri, Lopes, Massimo, van Attikum, Haico, Borst, Piet, Jonkers, Jos, Rottenberg, Sven
Format: Journal Article
Language:English
Published: United States 11.06.2018
Subjects:
Animals
BRCA1 Protein - genetics
BRCA1 Protein - metabolism
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Cell Line, Tumor
Female
Glycoside Hydrolases - antagonists & inhibitors
Glycoside Hydrolases - genetics
Glycoside Hydrolases - metabolism
Homologous Recombination - drug effects
Homologous Recombination - genetics
Humans
Mice, 129 Strain
Mice, Knockout
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - genetics
Ovarian Neoplasms - metabolism
Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors
Poly (ADP-Ribose) Polymerase-1 - genetics
Poly (ADP-Ribose) Polymerase-1 - metabolism
Poly ADP Ribosylation - drug effects
Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
Synthetic Lethal Mutations
PARG
PARP1
homologous recombination
PARP inhibitor
replication fork
BRCA1
drug resistance
BRCA2
PARylation
ISSN:1878-3686, 1878-3686
Online Access:Get more information
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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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ISSN:1878-3686
1878-3686
DOI:10.1016/j.ccell.2018.05.008