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

RJ Edmondson, F Middleton, M Patterson, C Elstob, S Fordham, A Herriott, M Wade, A McCormick, FEB May, J Allan, J Pollard, NJ Curtin

    Research output: Contribution to journalArticlepeer-review


    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.
    Original languageEnglish
    Pages (from-to)32396-32409
    Number of pages13
    Issue number32
    Publication statusPublished - 2015


    Dive into the research topics of 'Common cancer-associated imbalances in the DNA damage response confer sensitivity to single agent ATR inhibition'. Together they form a unique fingerprint.

    Cite this