Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma.
Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma.
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DOI：
10.1158/2159-8290.cd-15-1442
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发表时间：
2016-07
期刊：
影响因子：
28.2
通讯作者：
Bardeesy N
中科院分区：
文献类型：
--
作者：
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
肝内胆管细胞癌（ICC）是一种侵袭性肝胆管恶性肿瘤，表现出频繁的异柠檬酸脱氢酶（IDH 1/IDH 2）突变。通过对包括17种胆道癌在内的一大组癌细胞系进行高通量药物筛选，我们发现IDH突变型（IDHm）ICC细胞对多激酶抑制剂达沙替尼表现出惊人的反应，在682种实体瘤细胞系中具有最高的敏感性。使用无偏蛋白质组学捕获激活的激酶组和基于CRISPR/Cas9的基因组编辑引入达沙替尼耐药的“看门人”突变激酶，我们将SRC确定为IDHm ICC中的关键达沙替尼靶标。重要的是，达沙替尼治疗的IDHm异种移植物表现出明显的细胞凋亡和肿瘤消退。我们的研究结果表明，IDHm ICC细胞对SRC具有独特的依赖性，并表明达沙替尼可能对IDHm ICC具有治疗益处。此外，这些蛋白质组学和基因组编辑策略提供了一种系统的和广泛适用的方法来定义潜在药物反应性的激酶抑制剂的靶点。
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.