Format

Send to

Choose Destination
Nat Commun. 2016 Dec 13;7:13837. doi: 10.1038/ncomms13837.

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

Author information

1
The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK.
2
The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
3
Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
4
GZA Hospitals Sint-Augustinus, Wilrijk, Belgium and Center for Oncological Research, University of Antwerp, Oosterveldlaan 24, Wilrijk Antwerp 2610, Belgium.
5
Vertex Pharmaceuticals (Europe) Limited, Milton Park, Abingdon, Oxfordshire OX14 4RY, UK.

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.

Conflict of interest statement

P.M.R. and J.R.P. are paid employees of Vertex Pharmaceuticals. Part of this work has been funded by Vertex Pharmaceuticals as part of a Sponsored Research Agreement between Vertex and The Institute of Cancer Research, London.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center