Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality.

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; ... (2018). Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality. Cancer cell, 33(6), 1078-1093.e12. Cell Press 10.1016/j.ccell.2018.05.008

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Rottenberg, Sven

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health
600 Technology > 630 Agriculture

ISSN:

1535-6108

Publisher:

Cell Press

Language:

English

Submitter:

Monika Mumenthaler

Date Deposited:

11 Dec 2018 16:28

Last Modified:

01 Jul 2019 02:33

Publisher DOI:

10.1016/j.ccell.2018.05.008

PubMed ID:

29894693

Uncontrolled Keywords:

BRCA1 BRCA2 PARG PARP inhibitor PARP1 PARylation drug resistance homologous recombination replication fork

BORIS DOI:

10.7892/boris.122087

URI:

https://boris.unibe.ch/id/eprint/122087

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