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DNA replication vulnerabilities render ovarian cancer cells sensitive to poly(ADP-Ribose) glycohydrolase inhibitors
Pillay, Nisha Tighe, Anthony Nelson, Louisa Littler, Samantha Coulson-Gilmer, Camilla Bah, Nourdine Golder, Anya Bakker, B Spierings, D James, Dominic I
Pillay, Nisha
Tighe, Anthony
Nelson, Louisa
Littler, Samantha
Coulson-Gilmer, Camilla
Bah, Nourdine
Golder, Anya
Bakker, B
Spierings, D
James, Dominic I
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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.
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Date
2019
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Article
Citation
Pillay N, Tighe A, Nelson L, Littler S, Coulson-Gilmer C, Bah N, et al. DNA replication vulnerabilities render ovarian cancer cells sensitive to poly(ADP-Ribose) glycohydrolase inhibitors. Cancer Cell. 2019 Mar 18;35(3):519-33.