DNA replication vulnerabilities render ovarian cancer cells sensitive to poly(ADP-ribose) glycohydrolase inhibitors

Stephen Taylor; Nisha Pillay; Anthony Tighe; Louisa Nelson; Samantha Littler; Camilla Coulson-Gilmer; Nourdine Bah; Anya Golder; Dominic James; Kate Smith; Allan Jordan; Robert D. Morgan; Donald Ogilvie; Dean Jackson

doi:10.1016/j.ccell.2019.02.004

DNA replication vulnerabilities render ovarian cancer cells sensitive to poly(ADP-ribose) glycohydrolase inhibitors

Stephen Taylor, Nisha Pillay, Anthony Tighe, Louisa Nelson, Samantha Littler, Camilla Coulson-Gilmer, Nourdine Bah, Anya Golder, Dominic James, Kate Smith, Allan Jordan, Robert D. Morgan, Donald Ogilvie, Dean Jackson

The Christie Hospital NHS Foundation Trust

Research output: Contribution to journal › Article › peer-review

Abstract

Inhibitors of poly(ADP-ribose) polymerase (PARP) have demonstrated efficacy in women with BRCA-mutant ovarian cancer. However, because only 15-20% of cases harbour BRCA mutations, additional strategies are required. Here, we show that a subset of ovarian cancer cell lines and ex vivo models derived from patient biopsies are intrinsically sensitive to a first-in-class 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 DNA replication genes, 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.

Original language	English
Pages (from-to)	519-533
Journal	Cancer Cell\|Cancer Cell
Volume	35
Issue number	3
Early online date	18 Mar 2019
DOIs	https://doi.org/10.1016/j.ccell.2019.02.004
Publication status	Published - 2019

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Manchester Cancer Research Centre

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10.1016/j.ccell.2019.02.004Licence: CC BY

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Taylor, S., Pillay, N., Tighe, A., Nelson, L., Littler, S., Coulson-Gilmer, C., Bah, N., Golder, A., James, D., Smith, K., Jordan, A., Morgan, R. D., Ogilvie, D., & Jackson, D. (2019). DNA replication vulnerabilities render ovarian cancer cells sensitive to poly(ADP-ribose) glycohydrolase inhibitors. Cancer Cell|Cancer Cell, 35(3), 519-533. https://doi.org/10.1016/j.ccell.2019.02.004

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title = "DNA replication vulnerabilities render ovarian cancer cells sensitive to poly(ADP-ribose) glycohydrolase inhibitors",

abstract = "Inhibitors of poly(ADP-ribose) polymerase (PARP) have demonstrated efficacy in women with BRCA-mutant ovarian cancer. However, because only 15-20% of cases harbour BRCA mutations, additional strategies are required. Here, we show that a subset of ovarian cancer cell lines and ex vivo models derived from patient biopsies are intrinsically sensitive to a first-in-class 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 DNA replication genes, 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.",

author = "Stephen Taylor and Nisha Pillay and Anthony Tighe and Louisa Nelson and Samantha Littler and Camilla Coulson-Gilmer and Nourdine Bah and Anya Golder and Dominic James and Kate Smith and Allan Jordan and Morgan, {Robert D.} and Donald Ogilvie and Dean Jackson",

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doi = "10.1016/j.ccell.2019.02.004",

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journal = "Cancer Cell|Cancer Cell",

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Taylor, S, Pillay, N, Tighe, A , Nelson, L, Littler, S, Coulson-Gilmer, C, Bah, N, Golder, A, James, D, Smith, K, Jordan, A, Morgan, RD, Ogilvie, D & Jackson, D 2019, 'DNA replication vulnerabilities render ovarian cancer cells sensitive to poly(ADP-ribose) glycohydrolase inhibitors', Cancer Cell|Cancer Cell, vol. 35, no. 3, pp. 519-533. https://doi.org/10.1016/j.ccell.2019.02.004

TY - JOUR

T1 - DNA replication vulnerabilities render ovarian cancer cells sensitive to poly(ADP-ribose) glycohydrolase inhibitors

AU - Taylor, Stephen

AU - Pillay, Nisha

AU - Tighe, Anthony

AU - Nelson, Louisa

AU - Littler, Samantha

AU - Coulson-Gilmer, Camilla

AU - Bah, Nourdine

AU - Golder, Anya

AU - James, Dominic

AU - Smith, Kate

AU - Jordan, Allan

AU - Morgan, Robert D.

AU - Ogilvie, Donald

AU - Jackson, Dean

PY - 2019

Y1 - 2019

N2 - Inhibitors of poly(ADP-ribose) polymerase (PARP) have demonstrated efficacy in women with BRCA-mutant ovarian cancer. However, because only 15-20% of cases harbour BRCA mutations, additional strategies are required. Here, we show that a subset of ovarian cancer cell lines and ex vivo models derived from patient biopsies are intrinsically sensitive to a first-in-class 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 DNA replication genes, 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.

AB - Inhibitors of poly(ADP-ribose) polymerase (PARP) have demonstrated efficacy in women with BRCA-mutant ovarian cancer. However, because only 15-20% of cases harbour BRCA mutations, additional strategies are required. Here, we show that a subset of ovarian cancer cell lines and ex vivo models derived from patient biopsies are intrinsically sensitive to a first-in-class 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 DNA replication genes, 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.

U2 - 10.1016/j.ccell.2019.02.004

DO - 10.1016/j.ccell.2019.02.004

M3 - Article

SN - 1535-6108

VL - 35

SP - 519

EP - 533

JO - Cancer Cell|Cancer Cell

JF - Cancer Cell|Cancer Cell

IS - 3

ER -

DNA replication vulnerabilities render ovarian cancer cells sensitive to poly(ADP-ribose) glycohydrolase inhibitors

Abstract

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