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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Vydané v:	Cancer cell Ročník 33; číslo 6; s. 1078
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 11.06.2018
Predmet:	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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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.
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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ContentType	Journal Article
Copyright	Copyright © 2018 Elsevier Inc. All rights reserved.
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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
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PublicationYear	2018
References	31185216 - Cancer Cell. 2019 Jun 10;35(6):950-952. doi: 10.1016/j.ccell.2019.05.012.
References_xml	– reference: 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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