title: Mouse model of intrahepatic cholangiocarcinoma validates FIG-ROS as a potent fusion oncogene and therapeutic target.
abstract: Cholangiocarcinoma is the second most common primary liver cancer and responds poorly to existing therapies. Intrahepatic cholangiocarcinoma (ICC) likely originates from the biliary tree and develops within the hepatic parenchyma. We have generated a flexible orthotopic allograft mouse model of ICC that incorporates common genetic alterations identified in human ICC and histologically resembles the human disease. We examined the utility of this model to validate driver alterations in ICC and tested their suitability as therapeutic targets. Specifically, we showed that the fused-in-glioblastoma-c-ros-oncogene1 (FIG-ROS1(S); FIG-ROS) fusion gene dramatically accelerates ICC development and that its inactivation in established tumors has a potent antitumor effect. Our studies establish a versatile model of ICC that will be a useful preclinical tool and validate ROS1 fusions as potent oncoproteins and therapeutic targets in ICC and potentially other tumor types.
authors.affiliation: Cancer Biology and Genetics Program and Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Anna
authors.initials: A
authors.lastname: Saborowski
authors.forename: Michael
authors.initials: M
authors.lastname: Saborowski
authors.forename: Monika A
authors.initials: MA
authors.lastname: Davare
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms; D001653:Bile Ducts, Intrahepatic; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000628:therapy; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D018014:Gene Transfer Techniques; D016158:Genes, p53 / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D008113:Liver Neoplasms / Q000235:genetics* / Q000628:therapy; D051379:Mice; D009154:Mutation / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D034622:RNA Interference; D012190:Retroviridae
chemical_list: C577198:FIG-ROS1 fusion protein, human; D015514:Oncogene Proteins, Fusion; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)