Data from Synthetic Lethal Targeting of <i>ARID1A</i>-Mutant Ovarian Clear Cell Tumors with Dasatinib

Abstract

<div>Abstract<p>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, <i>ARID1A</i> mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both <i>in vitro</i> and <i>in vivo</i>, suggesting that this is a robust synthetic lethal interaction. The sensitivity of <i>ARID1A</i>-deficient cells to dasatinib was associated with G<sub>1</sub>–S cell-cycle arrest and was dependent upon both p21 and Rb. Using focused siRNA screens and kinase profiling, we showed that <i>ARID1A</i>-mutant OCCC tumor cells are addicted to the dasatinib target YES1. This suggests that dasatinib merits investigation for the treatment of patients with <i>ARID1A</i>-mutant OCCC. <i>Mol Cancer Ther; 15(7); 1472–84. ©2016 AACR</i>.</p></div>