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Ref Type Journal Article
PMID (27364904)
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 Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 15 7 2016 Jul 1472-84 Mol Cancer Ther
URL
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.

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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 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
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