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

Nisha Pillay; Anthony Tighe; Louisa Nelson; Samantha Littler; Camilla Coulson-Gilmer; Nourdine Bah; Anya Golder; Bjorn Bakker; Diana C J Spierings; Dominic I James; Kate M Smith; Allan M Jordan; Robert D Morgan; Donald J Ogilvie; Floris Foijer; Dean A Jackson; Stephen S Taylor

doi:10.1016/j.ccell.2019.02.004

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

Nisha Pillay
, Anthony Tighe
, Louisa Nelson
, Samantha Littler
, Camilla Coulson-Gilmer
, Nourdine Bah
, Anya Golder
, Bjorn Bakker
, Diana C J Spierings
, Dominic I James
, Kate M Smith
, Allan M Jordan
, Robert D Morgan
, Donald J Ogilvie
, Floris Foijer
, Dean A Jackson
, Stephen S Taylor

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

104 Citations (Scopus)

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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.

Original language	English
Pages (from-to)	519-533.e8
Number of pages	11
Journal	Cancer cell
Volume	35
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2019.02.004
Publication status	Published - 18-Mar-2019

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Pillay, N., Tighe, A., Nelson, L., Littler, S., Coulson-Gilmer, C., Bah, N., Golder, A., Bakker, B., Spierings, D. C. J., James, D. I., Smith, K. M., Jordan, A. M., Morgan, R. D., Ogilvie, D. J., Foijer, F., Jackson, D. A., & Taylor, S. S. (2019). DNA Replication Vulnerabilities Render Ovarian Cancer Cells Sensitive to Poly(ADP-Ribose) Glycohydrolase Inhibitors. Cancer cell, 35(3), 519-533.e8. https://doi.org/10.1016/j.ccell.2019.02.004

@article{25a39f4cbc3d4f4b8c5191778bb00274,

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, 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.",

author = "Nisha Pillay and Anthony Tighe and Louisa Nelson and Samantha Littler and Camilla Coulson-Gilmer and Nourdine Bah and Anya Golder and Bjorn Bakker and Spierings, \{Diana C J\} and James, \{Dominic I\} and Smith, \{Kate M\} and Jordan, \{Allan M\} and Morgan, \{Robert D\} and Ogilvie, \{Donald J\} and Floris Foijer and Jackson, \{Dean A\} and Taylor, \{Stephen S\}",

year = "2019",

month = mar,

day = "18",

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

language = "English",

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pages = "519--533.e8",

journal = "Cancer cell",

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Pillay, N, Tighe, A, Nelson, L, Littler, S, Coulson-Gilmer, C, Bah, N, Golder, A, Bakker, B, Spierings, DCJ, James, DI, Smith, KM, Jordan, AM, Morgan, RD, Ogilvie, DJ, Foijer, F, Jackson, DA & Taylor, SS 2019, 'DNA Replication Vulnerabilities Render Ovarian Cancer Cells Sensitive to Poly(ADP-Ribose) Glycohydrolase Inhibitors', Cancer cell, vol. 35, no. 3, pp. 519-533.e8. 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 - Pillay, Nisha

AU - Tighe, Anthony

AU - Nelson, Louisa

AU - Littler, Samantha

AU - Coulson-Gilmer, Camilla

AU - Bah, Nourdine

AU - Golder, Anya

AU - Bakker, Bjorn

AU - Spierings, Diana C J

AU - James, Dominic I

AU - Smith, Kate M

AU - Jordan, Allan M

AU - Morgan, Robert D

AU - Ogilvie, Donald J

AU - Foijer, Floris

AU - Jackson, Dean A

AU - Taylor, Stephen S

PY - 2019/3/18

Y1 - 2019/3/18

N2 - 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.

AB - 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.

U2 - 10.1016/j.ccell.2019.02.004

DO - 10.1016/j.ccell.2019.02.004

M3 - Article

C2 - 30889383

SN - 1535-6108

VL - 35

SP - 519-533.e8

JO - Cancer cell

JF - Cancer cell

IS - 3

ER -

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

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