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

Gogola, E., Duarte, A. A., de Ruiter, J. R., Wiegant, W. W., Schmid, J. A., de Bruijn, R., James, D. I., Llobet, S. G., Vis, D. J., Annunziato, S., van den Broek, B., Barazas, M., Kersbergen, A., van de Ven, M., Tarsounas, M., Ogilvie, D. J., van Vugt, M., Wessels, L. F. A., Bartkova, J., Gromova, I., Andujar-Sanchez, M., Bartek, J., Lopes, M., van Attikum, H., Borst, P., Jonkers, J. & Rottenberg, S., 11-Jun-2018, In : Cancer cell. 33, 6, p. 1078-1093e12 28 p.

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DOI

  • Ewa Gogola
  • Alexandra A. Duarte
  • Julian R. de Ruiter
  • Wouter W. Wiegant
  • Jonas A. Schmid
  • Roebi de Bruijn
  • Dominic I. James
  • Sergi Guerrero Llobet
  • Daniel J. Vis
  • Stefano Annunziato
  • Bram van den Broek
  • Marco Barazas
  • Ariena Kersbergen
  • Marieke van de Ven
  • Madalena Tarsounas
  • Donald J. Ogilvie
  • Marcel van Vugt
  • Lodewyk F. A. Wessels
  • Jirina Bartkova
  • Irina Gromova
  • Miguel Andujar-Sanchez
  • Jiri Bartek
  • Massimo Lopes
  • Haico van Attikum
  • Piet Borst
  • Jos Jonkers
  • Sven Rottenberg

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.

Original languageEnglish
Pages (from-to)1078-1093e12
Number of pages28
JournalCancer cell
Volume33
Issue number6
Publication statusPublished - 11-Jun-2018

    Keywords

  • DNA-DAMAGE-RESPONSE, REPLICATION FORK REVERSAL, CONDITIONAL MOUSE MODEL, POLY(ADP-RIBOSE) POLYMERASE, DEFICIENT CELLS, MAMMARY-TUMORS, BREAST-CANCER, HOMOLOGOUS RECOMBINATION, COMBINATION THERAPY, REPAIR

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