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

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

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  • Media type: E-Article
  • Title: Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib
  • Contributor: Miller, Rowan E.; Brough, Rachel; Bajrami, Ilirjana; Williamson, Chris T.; McDade, Simon; Campbell, James; Kigozi, Asha; Rafiq, Rumana; Pemberton, Helen; Natrajan, Rachel; Joel, Josephine; Astley, Holly; Mahoney, Claire; Moore, Jonathan D.; Torrance, Chris; Gordan, John D.; Webber, James T.; Levin, Rebecca S.; Shokat, Kevan M.; Bandyopadhyay, Sourav; Lord, Christopher J.; Ashworth, Alan
  • imprint: American Association for Cancer Research (AACR), 2016
  • Published in: Molecular Cancer Therapeutics
  • Language: English
  • DOI: 10.1158/1535-7163.mct-15-0554
  • ISSN: 1535-7163; 1538-8514
  • Keywords: Cancer Research ; Oncology
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title> <jats: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, 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.</jats:p>
  • Access State: Open Access