ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A.
Date
2016-12-13Author
Williamson, CT
Miller, R
Pemberton, HN
Jones, SE
Campbell, J
Konde, A
Badham, N
Rafiq, R
Brough, R
Gulati, A
Ryan, CJ
Francis, J
Vermulen, PB
Reynolds, AR
Reaper, PM
Pollard, JR
Ashworth, A
Lord, CJ
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
Cell Line, Tumor
Humans
Nuclear Proteins
Transcription Factors
Antineoplastic Agents
Apoptosis
RNA Interference
Cell Cycle Checkpoints
Ataxia Telangiectasia Mutated Proteins
Research team
Tumour Biology
Gene Function
Sarcoma Molecular Pathology
Language
eng
Date accepted
2016-11-03
License start date
2016-12-13
Citation
Nature communications, 2016, 7 pp. 13837 - ?
Publisher
NATURE PUBLISHING GROUP