American Association for Cancer Research
15357163mct150554-sup-152119_3_supp_3432717_n52752.pdf (5.85 MB)

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

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journal contribution
posted on 2023-04-03, 15:41 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

Supplementary Figure 1 ARID1A mutations in the panel of OCCC tumour cell line models with corresponding protein expression. Supplementary Figure 2 Un-cropped western blots from main and supplementary figures. Supplementary Figure 3 ARID1A selective effects from the high throughput drug screen. Supplementary Figure 4 Inhibitors of the PI3K/mTOR signalling pathway in the panel of OCCC cell lines and ARID1A selectivity. Supplementary Figure 5 Dasatinib is a synthetic lethal drug in ARID1A mutant OCCC tumour cell line models - see also Figure 2. Supplementary Figure 6 Dasatinib sensitivity in ARID1A mutant isogenic HCT116 colorectal tumour cell line model. Supplementary Figure 7 Dasatinib siRNA screen results. Supplementary Figure 8 Apoptosis assay in four OCCC cell line models, see also Figure 4. Supplementary Figure 9 Dasatinib sensitivity in ARID1A mutant OCCC is dependent upon G1/S checkpoint effectors, see also Figure 5. Supplementary Figure 10 Determining the optimal method of dasatinib delivery in vivo.


Cancer Research UK




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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