Mouse model of intrahepatic cholangiocarcinoma validates FIG–ROS as a potent fusion oncogene and therapeutic target

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 48; pp. 19513 - 19518
• Main Authors: Saborowski, Anna, Saborowski, Michael, Davare, Monika A., Druker, Brian J., Klimstra, David S., Lowe, Scott W.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26.11.2013; NATIONAL ACADEMY OF SCIENCES; National Acad Sciences
• Subjects: Animals; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biological Sciences; Cancer; Cancer therapies; Cell Line, Tumor; Cell lines; Cells; Cholangiocarcinoma; Cholangiocarcinoma - genetics; Cholangiocarcinoma - therapy; Disease Models, Animal; Gene Expression Regulation, Neoplastic - genetics; Gene Transfer Techniques; Genes, p53 - genetics; Genetic Therapy - methods; Genetics; Hepatocellular carcinoma; Hepatocytes; Histology; Liver; Liver cancer; Liver cells; Liver Neoplasms - genetics; Liver Neoplasms - therapy; Mathematical models; Mice; Mutation - genetics; Oncogene Proteins, Fusion - genetics; Oncology; Proto-Oncogene Proteins p21(ras) - genetics; Retroviridae; RNA Interference; Tumor cell line; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1311707110

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.