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|Ref Type||Journal Article|
|Authors||Miller RE, Brough R, Bajrami I, Williamson CT, McDade S, Campbell J, Kigozi A, Rafiq R, Pemberton H, Natrajan R, Joel J, Astley H, Mahoney C, Moore JD, Torrance C, Gordan JD, Webber JT, Levin RS, Shokat KM, Bandyopadhyay S, Lord CJ, Ashworth A|
|Title||Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction. The sensitivity of ARID1A-deficient cells to dasatinib was associated with G1-S cell-cycle arrest and was dependent upon both p21 and Rb. Using focused siRNA screens and kinase profiling, we showed that ARID1A-mutant OCCC tumor cells are addicted to the dasatinib target YES1. This suggests that dasatinib merits investigation for the treatment of patients with ARID1A-mutant OCCC. Mol Cancer Ther; 15(7); 1472-84. ©2016 AACR.|
|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||Dasatinib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, Sprycel (dasatinib) resulted in decreased cell growth of ovarian clear cell carcinoma (OCCC) cells harboring an ARID1A mutation in culture and anti-tumor activity in cell line xenograft models of OCCC (PMID: 27364904).||27364904|
|ARID1A Q456*||colorectal cancer||sensitive||Dasatinib||Preclinical - Cell culture||Actionable||In a preclinical study, a colorectal cancer cell line homozygously expressing ARID1A Q456* demonstrated sensitivity to treatment with Sprycel (dasatinib) in culture (PMID: 27364904).||27364904|