Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma

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

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.