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Cancer Cell. 2018 Jun 11;33(6):1078-1093.e12. doi: 10.1016/j.ccell.2018.05.008.

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

Author information

1
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, Amsterdam 1066CX, the Netherlands.
2
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, Amsterdam 1066CX, the Netherlands.
3
Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, the Netherlands.
4
Institute of Molecular Cancer Research, University of Zurich, Zurich CH-8057, Switzerland.
5
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK.
6
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen 9723GZ, the Netherlands.
7
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, Amsterdam 1066CX, the Netherlands.
8
Division of Cell Biology and BioImaging Facility, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands.
9
Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands.
10
Mouse Clinic for Cancer and Aging (MCCA), Preclinical Intervention Unit, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands.
11
CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
12
Danish Cancer Society Research Center, Copenhagen 2100, Denmark; Karolinska Institute, Department of Medical Biochemistry and Biophysics, Division of Genome Biology, Science for Life Laboratory, Stockholm 171 77, Sweden.
13
Danish Cancer Society Research Center, Copenhagen 2100, Denmark.
14
Pathology Department, Complejo Hospt. Univ. Insular Materno Infantil, Las Palmas, Gran Canaria, Spain.
15
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, Amsterdam 1066CX, the Netherlands. Electronic address: j.jonkers@nki.nl.
16
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern 3012, Switzerland. Electronic address: sven.rottenberg@vetsuisse.unibe.ch.

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.

KEYWORDS:

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

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