RRC ID 61776
Author Saha SK, Gordan JD, Kleinstiver BP, Vu P, Najem MS, Yeo JC, Shi L, Kato Y, Levin RS, Webber JT, Damon LJ, Egan RK, Greninger P, McDermott U, Garnett MJ, Jenkins RL, Rieger-Christ KM, Sullivan TB, Hezel AF, Liss AS, Mizukami Y, Goyal L, Ferrone CR, Zhu AX, Joung JK, Shokat KM, Benes CH, Bardeesy N.
Title Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma.
Journal Cancer Discov
Abstract UNLABELLED: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.
Volume 6(7)
Pages 727-39
Published 2016-7-1
DOI 10.1158/2159-8290.CD-15-1442
PII 2159-8290.CD-15-1442
PMID 27231123
PMC PMC5458737
MeSH Animals Bile Duct Neoplasms / genetics Bile Duct Neoplasms / metabolism Cell Line, Tumor Cell Proliferation Cholangiocarcinoma / genetics* Cholangiocarcinoma / metabolism* Cluster Analysis Dasatinib / pharmacology* Disease Models, Animal Drug Resistance, Neoplasm / genetics* Gene Expression Profiling Humans Isocitrate Dehydrogenase / genetics* Mice Mutation* Xenograft Model Antitumor Assays src-Family Kinases / metabolism*
IF 29.497
Human and Animal Cells HuCCT1(RCB1960) G-415(RCB2640) RBE(RCB1292) SSP-25(RCB1293) TFK-1(RCB2537) TGBC14TKB(RCB1186) YSCCC(RCB1549) TKKK(RCB1907)