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Cancer Cell. 2019 Mar 18;35(3):519-533.e8. doi: 10.1016/j.ccell.2019.02.004.

DNA Replication Vulnerabilities Render Ovarian Cancer Cells Sensitive to Poly(ADP-Ribose) Glycohydrolase Inhibitors.

Author information

1
Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, 555 Wilmslow Road, Manchester M20 4GJ, UK.
2
European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands.
3
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
4
Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, 555 Wilmslow Road, Manchester M20 4GJ, UK; The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK.
5
Division of Molecular and Cellular Function, Faculty of Biology, Medicine and Health, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PL, UK.
6
Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, 555 Wilmslow Road, Manchester M20 4GJ, UK. Electronic address: stephen.taylor@manchester.ac.uk.

Abstract

Inhibitors of poly(ADP-ribose) polymerase (PARP) have demonstrated efficacy in women with BRCA-mutant ovarian cancer. However, only 15%-20% of ovarian cancers harbor BRCA mutations, therefore additional therapies are required. Here, we show that a subset of ovarian cancer cell lines and ex vivo models derived from patient biopsies are sensitive to a poly(ADP-ribose) glycohydrolase (PARG) inhibitor. Sensitivity is due to underlying DNA replication vulnerabilities that cause persistent fork stalling and replication catastrophe. PARG inhibition is synthetic lethal with inhibition of DNA replication factors, allowing additional models to be sensitized by CHK1 inhibitors. Because PARG and PARP inhibitor sensitivity are mutually exclusive, our observations demonstrate that PARG inhibitors have therapeutic potential to complement PARP inhibitor strategies in the treatment of ovarian cancer.

KEYWORDS:

DNA damage; HGSOC; PARG; PARP; TIMELESS; replication catastrophe; γH2AX

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