{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T21:44:20Z","timestamp":1790199860250,"version":"4.1.0"},"reference-count":48,"publisher":"American Association for Cancer Research (AACR)","issue":"7","content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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 \u201cgatekeeper\u201d 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.<\/jats:p>\n                  <jats:p>Significance:\u2008IDH 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\u201339. \u00a92016 AACR.<\/jats:p>\n                  <jats:p>This article is highlighted in the In This Issue feature, p. 681<\/jats:p>","DOI":"10.1158\/2159-8290.cd-15-1442","type":"journal-article","created":{"date-parts":[[2016,5,26]],"date-time":"2016-05-26T23:04:03Z","timestamp":1464303843000},"page":"727-739","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":145,"title":["Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma"],"prefix":"10.1158","volume":"6","author":[{"given":"Supriya K.","family":"Saha","sequence":"first","affiliation":[{"name":"1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Gordan","sequence":"additional","affiliation":[{"name":"2Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin P.","family":"Kleinstiver","sequence":"additional","affiliation":[{"name":"3Molecular Pathology Unit, Center for Cancer Research, and Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, Massachusetts."},{"name":"4Department of Pathology, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phuong","family":"Vu","sequence":"additional","affiliation":[{"name":"1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mortada S.","family":"Najem","sequence":"additional","affiliation":[{"name":"1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, 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California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James T.","family":"Webber","sequence":"additional","affiliation":[{"name":"2Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah J.","family":"Damon","sequence":"additional","affiliation":[{"name":"1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina K.","family":"Egan","sequence":"additional","affiliation":[{"name":"1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Greninger","sequence":"additional","affiliation":[{"name":"1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, 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