PT  - JOURNAL ARTICLE
AU  - Miller, Rowan E.
AU  - Brough, Rachel
AU  - Bajrami, Ilirjana
AU  - Williamson, Chris T.
AU  - McDade, Simon
AU  - Campbell, James
AU  - Kigozi, Asha
AU  - Rafiq, Rumana
AU  - Pemberton, Helen
AU  - Natrajan, Rachel
AU  - Joel, Josephine
AU  - Astley, Holly
AU  - Mahoney, Claire
AU  - Moore, Jonathan D.
AU  - Torrance, Chris
AU  - Gordan, John D.
AU  - Webber, James T.
AU  - Levin, Rebecca S.
AU  - Shokat, Kevan M.
AU  - Bandyopadhyay, Sourav
AU  - Lord, Christopher J.
AU  - Ashworth, Alan
TI  - Synthetic Lethal Targeting of <em>ARID1A</em>-Mutant Ovarian Clear Cell Tumors with Dasatinib
AID  - 10.1158/1535-7163.MCT-15-0554
DP  - 2016 Jul 01
TA  - Molecular Cancer Therapeutics
PG  - 1472--1484
VI  - 15
IP  - 7
4099  - http://mct.aacrjournals.org/content/15/7/1472.short
4100  - http://mct.aacrjournals.org/content/15/7/1472.full
SO  - Mol Cancer Ther2016 Jul 01; 15
AB  - 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.