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Ref Type Journal Article
PMID (27958275)
Authors 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
Title ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A.
Journal Nature communications
Vol 7
Issue
Date 2016 Dec 13
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ARID1A mutant ovarian clear cell carcinoma sensitive Berzosertib Preclinical - Cell line xenograft Actionable In a preclinical study, Berzosertib (VX-970) treatment in ovarian clear cell carcinoma cells harboring an ARID1A mutation resulted in decreased cell survival and induction of DNA damage and apoptosis in culture, and tumor growth inhibition in cell line xenograft models (PMID: 27958275). 27958275
ARID1A Q456* colorectal cancer sensitive Berzosertib Preclinical - Cell line xenograft Actionable In a preclinical study, Berzosertib (VX-970) treatment in colorectal cancer cells homozygous for ARID1A Q456* resulted in decreased cell survival in culture, and tumor growth inhibition in cell line xenograft models (PMID: 27958275). 27958275
ARID1A mutant ovarian clear cell carcinoma sensitive VE-821 Preclinical - Cell culture Actionable In a preclinical study, ovarian clear cell carcinoma cells harboring an ARID1A mutation were sensitive to VE-821 in in vitro assays, demonstrating decreased cell survival (PMID: 27958275). 27958275
ARID1A Q456* colorectal cancer sensitive VE-821 Preclinical - Cell culture Actionable In a preclinical study, colorectal cancer cells homozygous for ARID1A Q456* were sensitive to VE-821 in in vitro assays, demonstrating decrease cell survival (PMID: 27958275). 27958275