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Targeting ATR in cancer

Nature Reviews Cancervolume 18pages586595 (2018) | Download Citation

Abstract

The chemical treatment of cancer started with the realization that DNA damaging agents such as mustard gas present notable antitumoural properties. Consequently, early drug development focused on genotoxic chemicals, some of which are still widely used in the clinic. However, the efficacy of such therapies is often limited by the side effects of these drugs on healthy cells. A refinement to this approach is to use compounds that can exploit the presence of DNA damage in cancer cells. Given that replication stress (RS) is a major source of genomic instability in cancer, targeting the RS-response kinase ataxia telangiectasia and Rad3-related protein (ATR) has emerged as a promising alternative. With ATR inhibitors now entering clinical trials, we here revisit the biology behind this strategy and discuss potential biomarkers that could be used for a better selection of patients who respond to therapy.

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Acknowledgements

Research was funded by Fundación Botín, by Banco Santander through its Santander Universities Global Division and by grants from the Spanish Ministry of Economy and Competitiveness (MINECO) (SAF2014-59498-R and SAF2014-57791-REDC); these projects were co-financed with European Regional Development funds, the Swedish Research council, Cancerfonden (CAN 2015/674) and the European Research Council (ERC-617840) to O.F.-C. and by a grant from MINECO (BFU2014-55168-JIN) that is co-funded with European Regional Development funds to E.L.

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Nature Reviews Cancer thanks A. Aguilera, D. Durocher and the anonymous reviewer(s) for their contribution to the peer review of this work.

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Affiliations

  1. Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    • Emilio Lecona
    •  & Oscar Fernandez-Capetillo
  2. Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden

    • Oscar Fernandez-Capetillo

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Contributions

O.F.-C. and E.L. researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

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The authors declare no competing interests.

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Correspondence to Oscar Fernandez-Capetillo.

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https://doi.org/10.1038/s41568-018-0034-3