ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A

Chris T. Williamson, Rowan Miller, Helen N. Pemberton, Samuel E. Jones, James Campbell, Asha Konde, Nicholas Badham, Rumana Rafiq, Rachel Brough, Aditi Gulati, Colm J. Ryan, Jeff Francis, Peter B. Vermulen, Andrew R. Reynolds, Philip M. Reaper, John R. Pollard, Alan Ashworth () and Christopher J. Lord ()
Additional contact information
Chris T. Williamson: The CRUK Gene Function Laboratory, The Institute of Cancer Research
Rowan Miller: The CRUK Gene Function Laboratory, The Institute of Cancer Research
Helen N. Pemberton: The CRUK Gene Function Laboratory, The Institute of Cancer Research
Samuel E. Jones: The CRUK Gene Function Laboratory, The Institute of Cancer Research
James Campbell: The CRUK Gene Function Laboratory, The Institute of Cancer Research
Asha Konde: The CRUK Gene Function Laboratory, The Institute of Cancer Research
Nicholas Badham: The CRUK Gene Function Laboratory, The Institute of Cancer Research
Rumana Rafiq: The CRUK Gene Function Laboratory, The Institute of Cancer Research
Rachel Brough: The CRUK Gene Function Laboratory, The Institute of Cancer Research
Aditi Gulati: The CRUK Gene Function Laboratory, The Institute of Cancer Research
Colm J. Ryan: Systems Biology Ireland, University College Dublin
Jeff Francis: The CRUK Gene Function Laboratory, The Institute of Cancer Research
Peter B. Vermulen: The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research
Andrew R. Reynolds: The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research
Philip M. Reaper: Vertex Pharmaceuticals (Europe) Limited, Milton Park
John R. Pollard: Vertex Pharmaceuticals (Europe) Limited, Milton Park
Alan Ashworth: The CRUK Gene Function Laboratory, The Institute of Cancer Research
Christopher J. Lord: The CRUK Gene Function Laboratory, The Institute of Cancer Research

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Identifying genetic biomarkers of synthetic lethal drug sensitivity effects provides one approach to the development of targeted cancer therapies. Mutations in ARID1A represent one of the most common molecular alterations in human cancer, but therapeutic approaches that target these defects are not yet clinically available. We demonstrate that defects in ARID1A sensitize tumour cells to clinical inhibitors of the DNA damage checkpoint kinase, ATR, both in vitro and in vivo. Mechanistically, ARID1A deficiency results in topoisomerase 2A and cell cycle defects, which cause an increased reliance on ATR checkpoint activity. In ARID1A mutant tumour cells, inhibition of ATR triggers premature mitotic entry, genomic instability and apoptosis. The data presented here provide the pre-clinical and mechanistic rationale for assessing ARID1A defects as a biomarker of single-agent ATR inhibitor response and represents a novel synthetic lethal approach to targeting tumour cells.

Date: 2016
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DOI: 10.1038/ncomms13837

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