Reference Detail

Ref Type

Journal Article

PMID

(27231123)

Authors

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	6	7	2016 Jul	727-39	Cancer Discov

URL

Abstract Text

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.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
IDH1 mutant	lung adenocarcinoma	resistant	Dasatinib	Preclinical	Actionable	In a preclinical study, lung adenocarcinoma cells harboring IDH1 mutations were resistant to Sprycel (dasatinib) in culture (PMID: 27231123).	27231123
IDH1 R132S	intrahepatic cholangiocarcinoma	sensitive	Saracatinib	Preclinical	Actionable	In a preclinical study, intrahepatic cholangiocarcinoma cells harboring IDH1 R132S demonstrated increased sensitivity to Saracatinib (AZD0530) induced growth inhibition compared to IDH1 wild-type cells in culture (PMID: 27231123).	27231123
IDH1 R132C	intrahepatic cholangiocarcinoma	sensitive	Saracatinib	Preclinical	Actionable	In a preclinical study, intrahepatic cholangiocarcinoma cells harboring IDH1 R132C demonstrated increased sensitivity to Saracatinib (AZD0530) induced growth inhibition compared to IDH1 wild-type cells in culture (PMID: 27231123).	27231123
IDH1 R132C	intrahepatic cholangiocarcinoma	sensitive	Dasatinib	Preclinical	Actionable	In a preclinical study, Sprycel (dasatinib) inhibited growth of intrahepatic cholangiocarcinoma cells harboring IDH1 R132C in culture, and suppressed tumor growth in PDX models (PMID: 27231123).	27231123
IDH1 R132S	intrahepatic cholangiocarcinoma	sensitive	Dasatinib	Preclinical	Actionable	In a preclinical study, intrahepatic cholangiocarcinoma cells harboring IDH1 R132S demonstrated increased sensitivity to Sprycel (dasatinib) induced growth inhibition compared to IDH1 wild-type cells in culture (PMID: 27231123).	27231123
IDH1 mutant	chondrosarcoma	resistant	Dasatinib	Preclinical	Actionable	In a preclinical study, chondrosarcoma cells harboring IDH1 mutations were resistant to Sprycel (dasatinib) in culture (PMID: 27231123).	27231123