Title |
Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma
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Published in |
Cancer Discovery, June 2016
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DOI | 10.1158/2159-8290.cd-15-1442 |
Pubmed ID | |
Authors |
Supriya K. Saha, John D. Gordan, Benjamin P. Kleinstiver, Phuong Vu, Mortada S. Najem, Jia-Chi Yeo, Lei Shi, Yasutaka Kato, Rebecca S. Levin, James T. Webber, Leah J. Damon, Regina K. Egan, Patricia Greninger, Ultan McDermott, Mathew J. Garnett, Roger L. Jenkins, Kimberly M. Rieger-Christ, Travis B. Sullivan, Aram F. Hezel, Andrew S. Liss, Yusuke Mizukami, Lipika Goyal, Cristina R. Ferrone, Andrew X. Zhu, J. Keith Joung, Kevan M. Shokat, Cyril H. Benes, Nabeel Bardeesy |
Abstract |
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 multi-kinase 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. |
X Demographics
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Unknown | 3 | 100% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 2 | 67% |
Scientists | 1 | 33% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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United Kingdom | 2 | 2% |
Unknown | 120 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 31 | 25% |
Student > Ph. D. Student | 15 | 12% |
Other | 10 | 8% |
Student > Postgraduate | 8 | 7% |
Student > Bachelor | 7 | 6% |
Other | 24 | 20% |
Unknown | 27 | 22% |
Readers by discipline | Count | As % |
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Medicine and Dentistry | 34 | 28% |
Biochemistry, Genetics and Molecular Biology | 21 | 17% |
Agricultural and Biological Sciences | 13 | 11% |
Pharmacology, Toxicology and Pharmaceutical Science | 10 | 8% |
Materials Science | 2 | 2% |
Other | 11 | 9% |
Unknown | 31 | 25% |