Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib.
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Date
2016-07-01Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
Animals
Humans
Mice
Adenocarcinoma, Clear Cell
Ovarian Neoplasms
Disease Models, Animal
Retinoblastoma Protein
Nuclear Proteins
Transcription Factors
Antineoplastic Agents
Protein Kinase Inhibitors
Drug Screening Assays, Antitumor
Drug Evaluation, Preclinical
Xenograft Model Antitumor Assays
Gene Expression Profiling
Apoptosis
Dose-Response Relationship, Drug
Female
Proto-Oncogene Proteins p21(ras)
Molecular Targeted Therapy
Dasatinib
Synthetic Lethal Mutations
Research team
Functional Genomics
Gene Function
Language
eng
Date accepted
2016-04-06
License start date
2016-07
Citation
Molecular cancer therapeutics, 2016, 15 (7), pp. 1472 - 1484
Publisher
AMER ASSOC CANCER RESEARCH