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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Veröffentlicht in:	Cancer cell Jg. 33; H. 6; S. 1078
Hauptverfasser:	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
Sprache:	Englisch
Veröffentlicht:	United States 11.06.2018
Schlagworte:	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
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1878-3686 1878-3686
DOI:	10.1016/j.ccell.2018.05.008