15357163mct150554-sup-152119_3_supp_3430445_y4y9yy.xlsx (51.38 kB)

Supplementary Table 2 from Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib

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posted on 2023-04-03, 15:40 authored by Rowan E. Miller, Rachel Brough, Ilirjana Bajrami, Chris T. Williamson, Simon McDade, James Campbell, Asha Kigozi, Rumana Rafiq, Helen Pemberton, Rachel Natrajan, Josephine Joel, Holly Astley, Claire Mahoney, Jonathan D. Moore, Chris Torrance, John D. Gordan, James T. Webber, Rebecca S. Levin, Kevan M. Shokat, Sourav Bandyopadhyay, Christopher J. Lord, Alan Ashworth

Compounds used in the high throughput drug screen in the panel of OCCC cell lines

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Cancer Research UK

FP7

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ARTICLE 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.

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Keywords

Gynecological Cancers Ovarian cancer Preclinical Models

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CC BY

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