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|Ref Type||Journal Article|
|Authors||Arai Y, Totoki Y, Hosoda F, Shirota T, Hama N, Nakamura H, Ojima H, Furuta K, Shimada K, Okusaka T, Kosuge T, Shibata T|
|Title||Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma.|
|Journal||Hepatology (Baltimore, Md.)|
|Abstract Text||Cholangiocarcinoma is an intractable cancer, with limited therapeutic options, in which the molecular mechanisms underlying tumor development remain poorly understood. Identification of a novel driver oncogene and applying it to targeted therapies for molecularly defined cancers might lead to improvements in the outcome of patients. We performed massively parallel whole transcriptome sequencing in eight specimens from cholangiocarcinoma patients without KRAS/BRAF/ROS1 alterations and identified two fusion kinase genes, FGFR2-AHCYL1 and FGFR2-BICC1. In reverse-transcriptase polymerase chain reaction (RT-PCR) screening, the FGFR2 fusion was detected in nine patients with cholangiocarcinoma (9/102), exclusively in the intrahepatic subtype (9/66, 13.6%), rarely in colorectal (1/149) and hepatocellular carcinoma (1/96), and none in gastric cancer (0/212). The rearrangements were mutually exclusive with KRAS/BRAF mutations. Expression of the fusion kinases in NIH3T3 cells activated MAPK and conferred anchorage-independent growth and in vivo tumorigenesis of subcutaneous transplanted cells in immune-compromised mice. This transforming ability was attributable to its kinase activity. Treatment with the fibroblast growth factor receptor (FGFR) kinase inhibitors BGJ398 and PD173074 effectively suppressed transformation.FGFR2 fusions occur in 13.6% of intrahepatic cholangiocarcinoma. The expression pattern of these fusions in association with sensitivity to FGFR inhibitors warrant a new molecular classification of cholangiocarcinoma and suggest a new therapeutic approach to the disease.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|FGFR2 AHCYL1||FGFR2 - AHCYL1||fusion||gain of function||FGFR2-AHCYL1 results from the fusion of FGFR2 and AHCYL1, resulting in the ability to activate MAPK signaling (PMID: 24122810) and induce transformation of cells in culture (PMID: 24122810, PMID: 35176488) and in animal models (PMID: 24122810). FGFR2-AHCYL1 has been identified in intrahepatic cholangiocarcinoma (PMID: 24122810).|
|FGFR2 BICC1||FGFR2 - BICC1||fusion||gain of function||FGFR2-BICC1 results from the fusion of FGFR2 and BICC1, resulting in the ability to induce oligomerization, Fgfr kinase activity, Mapk signaling and transformation of cells in culture and in animal models (PMID: 23558953, PMID: 24122810, PMID: 28416604). FGFR2-BICC1 has been identified in intrahepatic cholangiocarcinoma (PMID: 25608663, PMID: 31899106).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|FGFR2 - AHCYL1||Advanced Solid Tumor||sensitive||Infigratinib||Preclinical||Actionable||In a preclinical study, treatment with Truseltiq (infigratinib) prevented transformation of cells expressing FGFR2-AHCYL1 in culture (PMID: 24122810).||24122810|
|FGFR2 - BICC1||Advanced Solid Tumor||sensitive||Infigratinib||Preclinical||Actionable||In a preclinical study, treatment with Truseltiq (infigratinib) prevented transformation of cells expressing FGFR2-BICC1 in culture (PMID: 24122810).||24122810|
|FGFR2 - AHCYL1||Advanced Solid Tumor||sensitive||PD173074||Preclinical||Actionable||In a preclinical study, treatment with PD173074 prevented transformation of cells expressing FGFR2-AHCYL1 in culture (PMID: 24122810).||24122810|
|FGFR2 - BICC1||Advanced Solid Tumor||sensitive||PD173074||Preclinical||Actionable||In a preclinical study, treatment with PD173074 prevented transformation of cells expressing FGFR2-BICC1 in culture (PMID: 24122810).||24122810|