Oncotarget

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

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

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Oncotarget. 2015; 6:32396-32409. https://doi.org/10.18632/oncotarget.6136

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Abstract

Fiona K. Middleton1, Miranda J. Patterson1, Claire J. Elstob1, Sarah Fordham1, Ashleigh Herriott1, Mark A. Wade1, Aiste McCormick1, Richard Edmondson1, Felicity E.B. May1, James M. Allan1, John R. Pollard2 and Nicola J. Curtin1

1 Newcastle University, Northern Institute for Cancer Research, Newcastle upon Tyne, UK

2 Vertex Pharmaceuticals (Europe) Limited, Milton Park, Abingdon, Oxfordshire, UK

Correspondence to:

Nicola J. Curtin, email:

Keywords: ATR, p53, DNA damage response, DNA-PKcs, synthetic lethality

Received: April 07, 2015 Accepted: September 22, 2015 Published: October 15, 2015

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.


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