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

Author(s)
Williamson, Chris T.  
Miller, Rowan  
Pemberton, Helen N.  
Jones, Samuel E.  
Campbell, James  
Konde, Asha  
Badham, Nicholas  
Rafiq, Rumana  
Brough, Rachel  
Gulati, Aditi  
Ryan, Colm J.  
Francis, Jeff  
Vermulen, Peter B.  
Reynolds, Andrew R.  
Reaper, Philip M.  
Pollard, John R.  
Ashworth, Alan  
Lord, Christopher J.  
Uri
http://hdl.handle.net/10197/9203
Date Issued
2016-12-13
Date Available
2018-01-24T15:03:21Z
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.
Sponsorship
Health Research Board
Science Foundation Ireland
Wellcome Trust
Other Sponsorship
Breast Cancer Now
Cancer Research UK
Vertex Pharmaceuticals
National Health Service
Type of Material
Journal Article
Publisher
Springer Nature
Journal
Nature Communications
Volume
7
Copyright (Published Version)
2016 the Authors
Subjects

Targeted therapies

Tumour biomarkers

DOI
10.1038/ncomms13837
Language
English
Status of Item
Peer reviewed
This item is made available under a Creative Commons License
https://creativecommons.org/licenses/by-nc-nd/3.0/ie/
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ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A CRYAN TBC.pdf

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2.16 MB

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Adobe PDF

Checksum (MD5)

4ec6f844b0903ee85428d5b125e2bae3

Owning collection
SBI Research Collection
Mapped collections
Conway Institute Research Collection

Item descriptive metadata is released under a CC-0 (public domain) license: https://creativecommons.org/public-domain/cc0/.
All other content is subject to copyright.

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