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Chromosomal translocations involving  fibroblast growth factor receptor 2  ( FGFR2 ) gene at the breakpoints are common genetic lesions in intrahepatic cholangiocarcinoma (ICC) and the resultant fusion protein products have emerged as promising druggable targets. However, predicting the sensitivity of  FGFR2  fusions to FGFR kinase inhibitors is crucial to the prognosis of the ICC-targeted therapy. Here, we report identification of nine  FGFR2  translocations out of 173 (5.2%) ICC tumors. Although clinicopathologically these  FGFR2  translocation bearing ICC tumors are indistinguishable from the rest of the cohort, they are invariably of the mass-forming type originated from the small bile duct. We show that the protein products of  FGFR2  fusions can be classified into three subtypes based on the breaking positions of the fusion partners: the classical fusions that retain the tyrosine kinase (TK) and the Immunoglobulin (Ig)-like domains ( n  = 6); the sub-classical fusions that retain only the TK domain without the Ig-like domain ( n  = 1); and the non-classical fusions that lack both the TK and Ig-like domains ( n  = 2). We demonstrate that cholangiocarcinoma cells engineered to express the classical and sub-classical fusions show sensitivity to  FGFR -specific kinase inhibitors as evident by the suppression of MAPK/ERK and AKT/PI3K activities following the inhibitor treatment. Furthermore, the kinase-deficient mutant of the sub-classical fusion also lost its sensitivity to the FGFR-specific inhibitors. Taken together, our study suggests that it is essential to determine the breakpoint and type of  FGFR2  fusions in the small bile duct subtype of ICC for the targeted treatment.

Typing FGFR2 translocation determines the response to targeted therapy of intrahepatic cholangiocarcinomas