Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib
Data(s) |
01/07/2016
31/12/1969
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Resumo |
<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 G<sub>1</sub> -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.</p> |
Identificador |
http://dx.doi.org/10.1158/1535-7163.MCT-15-0554 http://www.scopus.com/inward/record.url?scp=84979211645&partnerID=8YFLogxK |
Idioma(s) |
eng |
Direitos |
info:eu-repo/semantics/embargoedAccess |
Fonte |
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 , Bandyopadhyay , S , Lord , C J & Ashworth , A 2016 , ' Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib ' Molecular Cancer Therapeutics , vol 15 , no. 7 , pp. 1472-1484 . DOI: 10.1158/1535-7163.MCT-15-0554 |
Palavras-Chave | #/dk/atira/pure/subjectarea/asjc/2700/2730 #Oncology #/dk/atira/pure/subjectarea/asjc/1300/1306 #Cancer Research |
Tipo |
article |