title: Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma.
abstract: 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.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Supriya K
authors.initials: SK
authors.lastname: Saha
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
authors.forename: John D
authors.initials: JD
authors.lastname: Gordan
authors.affiliation: Molecular Pathology Unit, Center for Cancer Research, and Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, Massachusetts. Department of Pathology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Kleinstiver
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Phuong
authors.initials: P
authors.lastname: Vu
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Mortada S
authors.initials: MS
authors.lastname: Najem
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jia-Chi
authors.initials: JC
authors.lastname: Yeo
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Levin
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
authors.forename: James T
authors.initials: JT
authors.lastname: Webber
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Damon
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Regina K
authors.initials: RK
authors.lastname: Egan
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Patricia
authors.initials: P
authors.lastname: Greninger
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Garnett
authors.affiliation: Department of Transplantation, Lahey Hospital and Medical Center, Burlington, Massachusetts.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Jenkins
authors.affiliation: Department of Translational Research, Lahey Hospital and Medical Center, Burlington, Massachusetts.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Rieger-Christ
authors.affiliation: Department of Translational Research, Lahey Hospital and Medical Center, Burlington, Massachusetts.
authors.forename: Travis B
authors.initials: TB
authors.lastname: Sullivan
authors.affiliation: University of Rochester School of Medicine, Rochester, New York.
authors.forename: Aram F
authors.initials: AF
authors.lastname: Hezel
authors.affiliation: Department of Surgery and the Andrew L. Warshaw, MD, Institute for Pancreatic Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Liss
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. Center for Clinical and Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Hokkaido, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Mizukami
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lipika
authors.initials: L
authors.lastname: Goyal
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Ferrone
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.affiliation: Molecular Pathology Unit, Center for Cancer Research, and Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, Massachusetts. Department of Pathology, Harvard Medical School, Boston, Massachusetts.
authors.forename: J Keith
authors.initials: JK
authors.lastname: Joung
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California. Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California.
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. nelbardeesy@partners.org cbenes@mgh.harvard.edu.
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. nelbardeesy@partners.org cbenes@mgh.harvard.edu.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000378:metabolism*; D016000:Cluster Analysis; D000069439:Dasatinib / Q000494:pharmacology*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D051379:Mice; D009154:Mutation; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D007521:Isocitrate Dehydrogenase; D019061:src-Family Kinases; D000069439:Dasatinib