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

doi:10.1016/j.ccell.2018.05.008

. 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

Ewa Gogola¹, Alexandra A Duarte¹, Julian R de Ruiter², Wouter W Wiegant³, Jonas A Schmid⁴, Roebi de Bruijn², Dominic I James⁵, Sergi Guerrero Llobet⁶, Daniel J Vis⁷, Stefano Annunziato¹, Bram van den Broek⁸, Marco Barazas¹, Ariena Kersbergen⁹, Marieke van de Ven¹⁰, Madalena Tarsounas¹¹, Donald J Ogilvie⁵, Marcel van Vugt⁶, Lodewyk F A Wessels⁷, Jirina Bartkova¹², Irina Gromova¹³, Miguel Andújar-Sánchez¹⁴, Jiri Bartek¹², Massimo Lopes⁴, Haico van Attikum³, Piet Borst⁹, Jos Jonkers¹⁵, Sven Rottenberg¹⁶

Affiliations

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.

PMID: 29894693
DOI: 10.1016/j.ccell.2018.05.008

Free article

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

Ewa Gogola et al. Cancer Cell. 2018.

Free article

. 2018 Jun 11;33(6):1078-1093.e12.

doi: 10.1016/j.ccell.2018.05.008.

Authors

Affiliations

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.

PMID: 29894693
DOI: 10.1016/j.ccell.2018.05.008

Erratum in

Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality.
Gogola E, Duarte AA, de Ruiter JR, Wiegant WW, Schmid JA, de Bruijn R, James DI, Llobet SG, Vis DJ, Annunziato S, van den Broek B, Barazas M, Kersbergen A, van de Ven M, Tarsounas M, Ogilvie DJ, van Vugt M, Wessels LFA, Bartkova J, Gromova I, Andújar-Sánchez M, Bartek J, Lopes M, van Attikum H, Borst P, Jonkers J, Rottenberg S. Gogola E, et al. Cancer Cell. 2019 Jun 10;35(6):950-952. doi: 10.1016/j.ccell.2019.05.012. Cancer Cell. 2019. PMID: 31185216 Free PMC article. No abstract available.

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

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

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