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 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
11.06.2018
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| Subjects: | |
| ISSN: | 1878-3686, 1878-3686 |
| Online Access: | Get more information |
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| 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. |
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| AbstractList | 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.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. 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. |
| Author | Rottenberg, Sven Gogola, Ewa van den Broek, Bram James, Dominic I Guerrero Llobet, Sergi Kersbergen, Ariena Wessels, Lodewyk F A Gromova, Irina van Vugt, Marcel Lopes, Massimo Barazas, Marco de Bruijn, Roebi Vis, Daniel J van de Ven, Marieke Annunziato, Stefano Bartek, Jiri Schmid, Jonas A Duarte, Alexandra A de Ruiter, Julian R Andújar-Sánchez, Miguel Jonkers, Jos Wiegant, Wouter W van Attikum, Haico Tarsounas, Madalena Ogilvie, Donald J Bartkova, Jirina Borst, Piet |
| Author_xml | – sequence: 1 givenname: Ewa surname: Gogola fullname: Gogola, Ewa organization: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, Amsterdam 1066CX, the Netherlands – sequence: 2 givenname: Alexandra A surname: Duarte fullname: Duarte, Alexandra A organization: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, Amsterdam 1066CX, the Netherlands – sequence: 3 givenname: Julian R surname: de Ruiter fullname: de Ruiter, Julian R organization: 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 – sequence: 4 givenname: Wouter W surname: Wiegant fullname: Wiegant, Wouter W organization: Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, the Netherlands – sequence: 5 givenname: Jonas A surname: Schmid fullname: Schmid, Jonas A organization: Institute of Molecular Cancer Research, University of Zurich, Zurich CH-8057, Switzerland – sequence: 6 givenname: Roebi surname: de Bruijn fullname: de Bruijn, Roebi organization: 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 – sequence: 7 givenname: Dominic I surname: James fullname: James, Dominic I organization: Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK – sequence: 8 givenname: Sergi surname: Guerrero Llobet fullname: Guerrero Llobet, Sergi organization: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen 9723GZ, the Netherlands – sequence: 9 givenname: Daniel J surname: Vis fullname: Vis, Daniel J organization: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, Amsterdam 1066CX, the Netherlands – sequence: 10 givenname: Stefano surname: Annunziato fullname: Annunziato, Stefano organization: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, Amsterdam 1066CX, the Netherlands – sequence: 11 givenname: Bram surname: van den Broek fullname: van den Broek, Bram organization: Division of Cell Biology and BioImaging Facility, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands – sequence: 12 givenname: Marco surname: Barazas fullname: Barazas, Marco organization: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, Amsterdam 1066CX, the Netherlands – sequence: 13 givenname: Ariena surname: Kersbergen fullname: Kersbergen, Ariena organization: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands – sequence: 14 givenname: Marieke surname: van de Ven fullname: van de Ven, Marieke organization: Mouse Clinic for Cancer and Aging (MCCA), Preclinical Intervention Unit, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands – sequence: 15 givenname: Madalena surname: Tarsounas fullname: Tarsounas, Madalena organization: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK – sequence: 16 givenname: Donald J surname: Ogilvie fullname: Ogilvie, Donald J organization: Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK – sequence: 17 givenname: Marcel surname: van Vugt fullname: van Vugt, Marcel organization: Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen 9723GZ, the Netherlands – sequence: 18 givenname: Lodewyk F A surname: Wessels fullname: Wessels, Lodewyk F A organization: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, Amsterdam 1066CX, the Netherlands – sequence: 19 givenname: Jirina surname: Bartkova fullname: Bartkova, Jirina organization: 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 – sequence: 20 givenname: Irina surname: Gromova fullname: Gromova, Irina organization: Danish Cancer Society Research Center, Copenhagen 2100, Denmark – sequence: 21 givenname: Miguel surname: Andújar-Sánchez fullname: Andújar-Sánchez, Miguel organization: Pathology Department, Complejo Hospt. Univ. Insular Materno Infantil, Las Palmas, Gran Canaria, Spain – sequence: 22 givenname: Jiri surname: Bartek fullname: Bartek, Jiri organization: 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 – sequence: 23 givenname: Massimo surname: Lopes fullname: Lopes, Massimo organization: Institute of Molecular Cancer Research, University of Zurich, Zurich CH-8057, Switzerland – sequence: 24 givenname: Haico surname: van Attikum fullname: van Attikum, Haico organization: Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, the Netherlands – sequence: 25 givenname: Piet surname: Borst fullname: Borst, Piet organization: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands – sequence: 26 givenname: Jos surname: Jonkers fullname: Jonkers, Jos email: j.jonkers@nki.nl organization: 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 – sequence: 27 givenname: Sven surname: Rottenberg fullname: Rottenberg, Sven email: sven.rottenberg@vetsuisse.unibe.ch organization: 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 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29894693$$D View this record in MEDLINE/PubMed |
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| Copyright | Copyright © 2018 Elsevier Inc. All rights reserved. |
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| DOI | 10.1016/j.ccell.2018.05.008 |
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| Keywords | PARG PARP1 homologous recombination PARP inhibitor replication fork BRCA1 drug resistance BRCA2 PARylation |
| Language | English |
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| PublicationTitle | Cancer cell |
| PublicationTitleAlternate | Cancer Cell |
| PublicationYear | 2018 |
| References | 31185216 - Cancer Cell. 2019 Jun 10;35(6):950-952. doi: 10.1016/j.ccell.2019.05.012. |
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| Snippet | Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers.... |
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| SubjectTerms | 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 |
| Title | Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality |
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