期刊
CANCER DISCOVERY
卷 6, 期 7, 页码 727-739出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-15-1442
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资金
- Translational Research Award from the V Foundation
- Target Cancer Foundation
- Gallagher Chair in Gastrointestinal Cancer Research at Massachusetts General Hospital
- NCI-Mentored Clinical Scientist Research Career Development Award [1K08CA194268-01]
- DF/HCC GI SPORE [P50CA127003]
- American Cancer Society Postdoctoral Grant
- Natural Sciences and Engineering Research Council of Canada Postdoctoral Fellowship
- Wellcome Trust [102696]
- NIH Director's Pioneer Award [DP1 GM105378]
- Editas Medicine
- Hera Testing Laboratories
- Poseida Therapeutics
- Transposagen Biopharmaceuticals
- Grants-in-Aid for Scientific Research [26670305] Funding Source: KAKEN
Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver bile duct malignancy exhibiting frequent isocitrate dehydrogenase (IDH1/IDH2) mutations. Through a high-throughput drug screen of a large panel of cancer cell lines, including 17 biliary tract cancers, we found that IDH mutant (IDHm) ICC cells demonstrate a striking response to the multikinase inhibitor dasatinib, with the highest sensitivity among 682 solid tumor cell lines. Using unbiased proteomics to capture the activated kinome and CRISPR/Cas9-based genome editing to introduce dasatinib-resistant gatekeeper mutant kinases, we identified SRC as a critical dasatinib target in IDHm ICC. Importantly, dasatinib-treated IDHm xenografts exhibited pronounced apoptosis and tumor regression. Our results show that IDHm ICC cells have a unique dependency on SRC and suggest that dasatinib may have therapeutic benefit against IDHm ICC. Moreover, these proteomic and genome-editing strategies provide a systematic and broadly applicable approach to define targets of kinase inhibitors underlying drug responsiveness. SIGNIFICANCE: IDH mutations define a distinct subtype of ICC, a malignancy that is largely refractory to current therapies. Our work demonstrates that IDHm ICC cells are hypersensitive to dasatinib and critically dependent on SRC activity for survival and proliferation, pointing to new therapeutic strategies against these cancers. (C) 2016 AACR.
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