Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib.
Loading...
Embargo End Date
ICR Authors
Authors
Miller, RE
Brough, R
Bajrami, I
Williamson, CT
McDade, S
Campbell, J
Kigozi, A
Rafiq, R
Pemberton, H
Natrajan, R
Joel, J
Astley, H
Mahoney, C
Moore, JD
Torrance, C
Gordan, JD
Webber, JT
Levin, RS
Shokat, KM
Bandyopadhyay, S
Lord, CJ
Ashworth, A
Brough, R
Bajrami, I
Williamson, CT
McDade, S
Campbell, J
Kigozi, A
Rafiq, R
Pemberton, H
Natrajan, R
Joel, J
Astley, H
Mahoney, C
Moore, JD
Torrance, C
Gordan, JD
Webber, JT
Levin, RS
Shokat, KM
Bandyopadhyay, S
Lord, CJ
Ashworth, A
Document Type
Journal Article
Date
2016-07-01
Date Accepted
2016-04-06
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 ARID1A-mutant OCCC. Mol Cancer Ther; 15(7); 1472-84. ©2016 AACR.
Citation
Molecular cancer therapeutics, 2016, 15 (7), pp. 1472 - 1484
Rights
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1535-7163
eISSN
1538-8514
Collections
Research Team
Functional Genomics
Gene Function
Gene Function