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

  • Gogola E Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, Amsterdam 1066CX, the Netherlands.
  • Duarte AA Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, Amsterdam 1066CX, the Netherlands.
  • de Ruiter JR 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.
  • Wiegant WW Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, the Netherlands.
  • Schmid JA Institute of Molecular Cancer Research, University of Zurich, Zurich CH-8057, Switzerland.
  • de Bruijn R 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.
  • James DI Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK.
  • Guerrero Llobet S Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen 9723GZ, the Netherlands.
  • Vis DJ Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, Amsterdam 1066CX, the Netherlands.
  • Annunziato S Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, Amsterdam 1066CX, the Netherlands.
  • van den Broek B Division of Cell Biology and BioImaging Facility, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands.
  • Barazas M Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, Amsterdam 1066CX, the Netherlands.
  • Kersbergen A Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands.
  • van de Ven M Mouse Clinic for Cancer and Aging (MCCA), Preclinical Intervention Unit, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands.
  • Tarsounas M CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
  • Ogilvie DJ Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK.
  • van Vugt M Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen 9723GZ, the Netherlands.
  • Wessels LFA Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands; Cancer Genomics Netherlands, Oncode Institute, Amsterdam 1066CX, the Netherlands.
  • Bartkova J 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.
  • Gromova I Danish Cancer Society Research Center, Copenhagen 2100, Denmark.
  • Andújar-Sánchez M Pathology Department, Complejo Hospt. Univ. Insular Materno Infantil, Las Palmas, Gran Canaria, Spain.
  • Bartek J 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.
  • Lopes M Institute of Molecular Cancer Research, University of Zurich, Zurich CH-8057, Switzerland.
  • van Attikum H Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZC, the Netherlands.
  • Borst P Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam 1066CX, the Netherlands.
  • Jonkers J 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.
  • Rottenberg S 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.
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  • 2018-06-13
Published in:
  • Cancer cell. - 2018
BRCA1
BRCA2
PARG
PARP inhibitor
PARP1
PARylation
drug resistance
homologous recombination
replication fork
Animals
BRCA1 Protein
Breast Neoplasms
Cell Line, Tumor
Female
Glycoside Hydrolases
Homologous Recombination
Humans
Mice, 129 Strain
Mice, Knockout
Ovarian Neoplasms
Poly (ADP-Ribose) Polymerase-1
Poly ADP Ribosylation
Poly(ADP-ribose) Polymerase Inhibitors
Synthetic Lethal Mutations
English 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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  • English
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bronze
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https://sonar.ch/global/documents/140574
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