TY - JOUR
T1 - Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib
AU - Miller, Rowan E.
AU - Brough, Rachel
AU - Bajrami, Ilirjana
AU - Williamson, Chris T.
AU - McDade, Simon
AU - Campbell, James
AU - Kigozi, Asha
AU - Rafiq, Rumana
AU - Pemberton, Helen
AU - Natrajan, Rachel
AU - Joel, Josephine
AU - Astley, Holly
AU - Mahoney, Claire
AU - Moore, Jonathan D.
AU - Torrance, Chris
AU - Gordan, John D.
AU - Webber, James T.
AU - Levin, Rebecca S.
AU - Shokat, Kevan M.
AU - Bandyopadhyay, Sourav
AU - Lord, Christopher J.
AU - Ashworth, Alan
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84979211645&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-15-0554
DO - 10.1158/1535-7163.MCT-15-0554
M3 - Article
AN - SCOPUS:84979211645
SN - 1535-7163
VL - 15
SP - 1472
EP - 1484
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 7
ER -