Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma
| Autor: | Aram F. Hezel, Nabeel Bardeesy, Cyril H. Benes, Jia-Chi Yeo, James T. Webber, Kevan M. Shokat, Travis Sullivan, Benjamin P. Kleinstiver, Roger L. Jenkins, Ultan McDermott, Yusuke Mizukami, Leah J. Damon, Regina K. Egan, Lei Shi, Supriya K. Saha, J. Keith Joung, John D. Gordan, Patricia Greninger, Rebecca S. Levin, Andrew S. Liss, Yasutaka Kato, Andrew X. Zhu, Kimberly M. Rieger-Christ, Mortada S. Najem, Lipika Goyal, Cristina R. Ferrone, Phuong Vu, Mathew J. Garnett |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Drug Resistance Dasatinib medicine.disease_cause Cholangiocarcinoma Mice 0302 clinical medicine hemic and lymphatic diseases 2.1 Biological and endogenous factors Cluster Analysis Kinome Aetiology Cancer Mutation Tumor Liver Disease Isocitrate Dehydrogenase src-Family Kinases Isocitrate dehydrogenase Oncology 5.1 Pharmaceuticals 030220 oncology & carcinogenesis Development of treatments and therapeutic interventions Biotechnology medicine.drug Proto-oncogene tyrosine-protein kinase Src Liver Cancer IDH1 Oncology and Carcinogenesis Biology IDH2 Article Cell Line 03 medical and health sciences Rare Diseases Cell Line Tumor medicine Animals Humans Digestive Diseases - (Gallbladder) Cell Proliferation Animal Gene Expression Profiling medicine.disease Xenograft Model Antitumor Assays Disease Models Animal Orphan Drug 030104 developmental biology Bile Duct Neoplasms Drug Resistance Neoplasm Disease Models Immunology Cancer research Neoplasm Digestive Diseases |
| Zdroj: | Cancer discovery, vol 6, iss 7 |
| ISSN: | 2159-8290 2159-8274 |
| Popis: | 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. Cancer Discov; 6(7); 727–39. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 681 |
| Databáze: | OpenAIRE |
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