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Targeting ATR for Cancer Therapy: Profile and Expectations for ATR Inhibitors

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Targeting the DNA Damage Response for Anti-Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

ATR is a highly versatile player in the DNA damage response (DDR) that signals DNA damage via CHK1 phosphorylation to the S and G2/M cell cycle checkpoints and to promote DNA repair. It is activated by ssDNA, principally occurring due to replication stress that is caused by unrepaired endogenous DNA damage or induced by a variety of anticancer chemotherapy and ionizing radiation. Since an almost ubiquitous feature of cancer cells is loss of G1 control, e.g., through p53 mutation, it is thought that their greater dependence on S and G2/M checkpoint function may render them more susceptible to ATR inhibition. ATR promotes homologous recombination DNA repair and inter-strand cross-link repair. Impairment of ATR function by genetic means or with inhibitors increases the sensitivity of cells to a wide variety of DNA damaging chemotherapy and radiotherapy, with the greatest sensitization observed with gemcitabine and cisplatin. Early inhibitors developed in the 1990s were weak and non-specific but the encouraging data led to the development of more potent and specific inhibitors. We review here the pre-clinical chemo- and radiosensitisation data obtained with these inhibitors that has led to the entry into clinical trial, the potential to combine ATR inhibitors with other DNA repair modulators, and identification of single-agent ATR inhibitor cytotoxicity in cells with activated oncogenes and particular defects in the DDR that may result in greater replication stress or dependence on ATR for survival.

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Authors and Affiliations

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

    Nicola Curtin

  2. Newcastle University Institute for Ageing, Medical School, Newcastle University, Newcastle upon Tyne, UK

    Nicola Curtin

  3. Vertex Pharmaceuticals (Europe) Ltd, Abingdon, Oxfordshire, UK

    John Pollard

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  1. Vertex Pharmaceuticals (Europe) Ltd, Abingdon, Oxfordshire, United Kingdom

    John Pollard

  2. Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom

    Nicola Curtin

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Curtin, N., Pollard, J. (2018). Targeting ATR for Cancer Therapy: Profile and Expectations for ATR Inhibitors. In: Pollard, J., Curtin, N. (eds) Targeting the DNA Damage Response for Anti-Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-75836-7_4

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