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PARG inhibition induces replication catastrophe in ovarian cancer cells with down-regulated DNA replication genes

C. Coulson-Gilmer, R.D. Morgan, L. Nelson, B. Barnes, J.C. McGrail, View ORCID ProfileS.S. Taylor
doi: https://doi.org/10.1101/2020.07.13.199968
C. Coulson-Gilmer
1Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, 555 Wilmslow Road, Manchester M20 4GJ, United Kingdom
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R.D. Morgan
1Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, 555 Wilmslow Road, Manchester M20 4GJ, United Kingdom
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L. Nelson
1Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, 555 Wilmslow Road, Manchester M20 4GJ, United Kingdom
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B. Barnes
1Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, 555 Wilmslow Road, Manchester M20 4GJ, United Kingdom
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J.C. McGrail
1Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, 555 Wilmslow Road, Manchester M20 4GJ, United Kingdom
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S.S. Taylor
1Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, 555 Wilmslow Road, Manchester M20 4GJ, United Kingdom
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  • ORCID record for S.S. Taylor
  • For correspondence: stephen.taylor@manchester.ac.uk
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Summary

The discovery that PARP1/2 inhibitors selectively kill BRCA mutant cells has led to a paradigm shift in the treatment of women with homologous recombination (HR)-deficient high-grade serous ovarian cancer (HGSOC), driving unprecedented improvements in progression-free and, more recently, overall survival. However, because most HGSOC cases are not HR-defective, and are therefore unlikely to benefit from PARPi-based therapies, additional strategies will be required to improve outcomes for women with HR-proficient disease. To develop novel therapeutic strategies, considerable attention is now being focused on inhibitors targeting PARG, the poly(ADP ribose) glycohydrolase that counterbalances PARP1/2 activity. Here we characterise ten ovarian cancer cell lines in response to the PARG inhibitor PDD00017273, hereafter PARGi. We demonstrate that six lines are resistant while four are sensitive, and that sensitivity correlates with several markers of persistent DNA replication stress, DNA damage and replication catastrophe, namely the accumulation of asymmetric DNA replication fibres, γH2AX and RPA foci, KAP1 and Chk1 phosphorylation, a pre-mitotic cell cycle block and, following prolonged exposure, a pan-nuclear γH2AX phenotype that indicates RPA exhaustion. We demonstrate that PARGi-sensitive cell lines have down-regulated DNA replication genes, including components of the fork protection complex, namely TIMELESS, TIPIN and CLASPIN. These observations suggest that a subset of HGSOC may respond to PARG inhibitors and that “replication stress” gene expression signature could serve as a predictive biomarker to guide the design of clinical trials.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 15, 2020.
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PARG inhibition induces replication catastrophe in ovarian cancer cells with down-regulated DNA replication genes
C. Coulson-Gilmer, R.D. Morgan, L. Nelson, B. Barnes, J.C. McGrail, S.S. Taylor
bioRxiv 2020.07.13.199968; doi: https://doi.org/10.1101/2020.07.13.199968
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PARG inhibition induces replication catastrophe in ovarian cancer cells with down-regulated DNA replication genes
C. Coulson-Gilmer, R.D. Morgan, L. Nelson, B. Barnes, J.C. McGrail, S.S. Taylor
bioRxiv 2020.07.13.199968; doi: https://doi.org/10.1101/2020.07.13.199968

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