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Common cancer-associated imbalances in the DNA damage response confer sensitivity to single agent ATR inhibition

Middleton, Fiona K.; Patterson, Miranda J.; Elstob, Claire J.; Fordham, Sarah; Herriott, Ashleigh; Wade, Mark A.; McCormick, Aiste; Edmondson, Richard; May, Felicity E.B.; Allan, James M.; Pollard, John R.; Curtin, Nicola J.

Authors

Fiona K. Middleton

Miranda J. Patterson

Claire J. Elstob

Sarah Fordham

Ashleigh Herriott

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Dr Mark Wade M.Wade@hull.ac.uk
Senior Lecturer in Molecular Genetics

Aiste McCormick

Richard Edmondson

Felicity E.B. May

James M. Allan

John R. Pollard

Nicola J. Curtin



Abstract

ATR is an attractive target in cancer therapy because it signals replication stress and DNA lesions for repair and to S/G2 checkpoints. Cancer-specific defects in the DNA damage response (DDR) may render cancer cells vulnerable to ATR inhibition alone. We determined the cytotoxicity of the ATR inhibitor VE-821 in isogenically matched cells with DDR imbalance. Cell cycle arrest, DNA damage accumulation and repair were determined following VE-821 exposure. Defects in homologous recombination repair (HRR: ATM, BRCA2 and XRCC3) and base excision repair (BER: XRCC1) conferred sensitivity to VE-821. Surprisingly, the loss of different components of the trimeric non-homologous end-joining (NHEJ) protein DNA-PK had opposing effects. Loss of the DNA-binding component, Ku80, caused hypersensitivity to VE-821, but loss of its partner catalytic subunit, DNA-PKcs, did not. Unexpectedly, VE-821 was particularly cytotoxic to human and hamster cells expressing high levels of DNA-PKcs. High DNA-PKcs was associated with replicative stress and activation of the DDR. VE-821 suppressed HRR, determined by RAD51 focus formation, to a greater extent in cells with high DNA-PKcs. Defects in HRR and BER and high DNA-PKcs expression, that are common in cancer, confer sensitivity to ATR inhibitor monotherapy and may be developed as predictive biomarkers for personalised medicine.

Citation

Middleton, F. K., Patterson, M. J., Elstob, C. J., Fordham, S., Herriott, A., Wade, M. A., …Curtin, N. J. (2015). Common cancer-associated imbalances in the DNA damage response confer sensitivity to single agent ATR inhibition. Oncotarget, 6(32), 32396-32409. https://doi.org/10.18632/oncotarget.6136

Journal Article Type Article
Acceptance Date Sep 22, 2015
Online Publication Date Oct 16, 2015
Publication Date Oct 20, 2015
Deposit Date Feb 4, 2019
Publicly Available Date Mar 29, 2024
Journal Oncotarget
Print ISSN 1949-2553
Electronic ISSN 1949-2553
Publisher Impact Journals
Peer Reviewed Peer Reviewed
Volume 6
Issue 32
Pages 32396-32409
DOI https://doi.org/10.18632/oncotarget.6136
Keywords ATR; p53; DNA damage response; DNA-PKcs; Synthetic lethality
Public URL https://hull-repository.worktribe.com/output/1271275
Publisher URL http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=6136&pubmed-linkout=1

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Copyright Statement
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited





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