Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib.

Rowan Miller ,Josephine Joel,Rebecca S Levin,Kevan M Shokat,Alan Ashworth,Rumana Rafiq,Holly Astley,Claire Mahoney,Helen Pemberton,Ilirjana Bajrami,James Campbell,John D Gordan,Jonathan D Moore,Chris Torrance,Asha Kigozi,Christopher J Lord,James T Webber,Chris T Williamson,Sourav Bandyopadhyay,Rachel Brough,Simon S Mcdade ,Rachael Natrajan

doi:10.1158/1535-7163.mct-15-0554

Abstract

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.

Highlights

Ovarian clear cell carcinomas (OCCC) comprise between 5 and 25% of all epithelial ovarian cancers and are often associated with endometriosis [1]
In the work presented here, we have attempted to understand drug sensitivities associated with ARID1A mutation in ovarian clear cell carcinomas (OCCC) by using a functional genomics approach
This has led us to the identification of dasatinib as a candidate synthetic lethal drug in ARID1Amutant OCCC

Summary

Introduction

Ovarian clear cell carcinomas (OCCC) comprise between 5 and 25% of all epithelial ovarian cancers and are often associated with endometriosis [1]. Comprehensive DNA sequencing of OCCCs has led to the identification of likely driver mutations in this disease [4, 5]. The most commonly recurrent genetic event in OCCC is somatic mutation in the tumor suppressor gene ARID1A Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). Torrance: PhoreMost, 23 Cambridge Science Park, Milton Road, Cambridge CB4 0EY, United Kingdom; and current address for A. Ashworth: UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158

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