Journal
CANCER CELL
Volume 35, Issue 3, Pages 519-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2019.02.004
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Funding
- Cancer Research UK [C1422/A19842]
- Wellcome Trust [109329/Z/15/Z]
- Medical Research Council [MR/L006839/1]
- Irshad Akhtar Memorial PhD Scholarship
- Netherlands Organisation for Scientific Research, The Netherlands (NWO) TOP grant [91215003]
- Wellcome Trust [109329/Z/15/Z] Funding Source: Wellcome Trust
- MRC [MR/L006839/1] Funding Source: UKRI
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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.
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