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.C holangiocarcinoma, the second most common primary liver cancer, has a dismal prognosis due to its poor responsiveness to existing therapies. It represents 10-25% of primary liver cancers worldwide (1), but is more frequent in Asia, due to a higher prevalence of risk factors such as parasitic infections, biliary-duct cysts, hepatolithiasis, and primary sclerosing cholangitis (2). Intrahepatic cholangiocarcinoma (ICC) develops within the liver parenchyma, shows markers of cholangiocyte differentiation, including positivity for cytokeratin 19, and leads to abundant stromal desmoplasia. Whereas surgical resection can be curative, most patients are not eligible for this procedure due to advanced disease, and no effective systemic therapy has been developed to date (3, 4).Sequencing efforts are beginning to generate in-depth information about the somatic alterations that occur in cholangiocarcinoma. Among the most frequently mutated genes are the tumor suppressor tumor protein p53 (TP53) (37-44%) (5, 6) and the kirsten rat sarcoma viral oncogene homolog (KRAS) (17-54%) (6-8), although mutations in MLL3 and SMAD4 are also common (15% and 17% of cases, respectively) (6). Despite their high mutational frequency, none of these signature genes is amenable to targeted therapy.Recently, the mutational spectrum of cholangiocarcinoma has been extended by the identification of ROS1 fusions in nearly 9% of cholangiocarcinoma patients (9). Oncogenic fusion kinases involving the orphan receptor tyrosine kinase ROS1 have been previously reported at low frequency in lung adenocarcinoma and glioblastoma and result from chromosomal rearrangements that lead to constitutive activation of the ROS1 kinase activity. Consequently, ROS1 presents a potential drug target for a subset of patients with ICC.Mouse models have proven a powerful tool for understanding the relationship between cancer genetics and tumor behavior, but only a few genetically engineered mouse models (GEMMs) of ICC exist and many display a mixed ICC/hepatocellular carcinoma (HCC) histology (10-13). A histopathologica...

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

“…Both plastic stents and self-expandable metallic stents can be utilized, but self-expandable metallic stents seem to offer several advantages, including higher patency duration than plastic stents 264 . 267,268 and fusion genes 68,74,79,269 . Targeted anti-fibrotic therapy is also under investigation 183 .…”

Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma

“…Expression of FIG-ROS1 in NIH3T3 cells conferred transforming ability both in vitro and in vivo, which could be inhibited by specific targeting (77). Furthermore, the oncogenic potential of FIG-ROS has been recently validated in an orthotopic allograft mouse iCCA model harboring KRAS and TP53 mutations (78). FIG-ROS alone was also able to promote tumorigenesis, although with reduced penetrance and longer latency.…”

Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications

“…Its role as an oncogenic driver and potential therapeutic target has been recently validated in preclinical studies, where its inactivation led to a potent anti-tumor effect (80). While its role as a potential therapeutic target has been confirmed in other solid tumor malignancies, notably non-small cell lung cancer (81), further validation will be required to assess its frequency in BC in addition to assessing its relevancy as a potential targetable mutation in patients exhibiting ROS1 fusions.…”