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

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 BandyopadhyayChristopher J. Lord*, Alan Ashworth

*Corresponding author for this work

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41 Citations (Scopus)
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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 ARID1Amutant OCCC. Mol Cancer Ther; 15(7); 1472-84. Ó2016 AACR.

Original languageEnglish
Pages (from-to)1472-1484
Number of pages13
JournalMolecular Cancer Therapeutics
Volume15
Issue number7
DOIs
Publication statusPublished - 01 Jul 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Miller, R. E., Brough, R., Bajrami, I., Williamson, C. T., McDade, S., Campbell, J., Kigozi, A., Rafiq, R., Pemberton, H., Natrajan, R., Joel, J., Astley, H., Mahoney, C., Moore, J. D., Torrance, C., Gordan, J. D., Webber, J. T., Levin, R. S., Shokat, K. M., ... Ashworth, A. (2016). Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib. Molecular Cancer Therapeutics, 15(7), 1472-1484. https://doi.org/10.1158/1535-7163.MCT-15-0554