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Typing FGFR2 translocation determines the response to targeted therapy of intrahepatic cholangiocarcinomas
Xiaohong Pu1, Qing Ye2,3, Jing Cai4
1Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu Province, China.
Abstract:
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.
Insights
Identifying fibroblast growth factor receptor 2 (FGFR2) fusion types in intrahepatic cholangiocarcinoma (ICC) is key for targeted therapy. Classical and sub-classical FGFR2 fusions respond to FGFR kinase inhibitors, unlike non-classical types.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chromosomal translocations involving the fibroblast growth factor receptor 2 (FGFR2) gene are frequent in intrahepatic cholangiocarcinoma (ICC).
- FGFR2 fusion proteins are promising therapeutic targets in ICC, but predicting treatment response is critical.
Purpose of the Study:
- To identify and classify FGFR2 fusions in ICC.
- To investigate the sensitivity of different FGFR2 fusion subtypes to FGFR kinase inhibitors.
- To correlate FGFR2 fusion characteristics with therapeutic response in ICC.
Main Methods:
- Screening of 173 ICC tumors for FGFR2 translocations.
- Classification of FGFR2 fusion protein products based on retained domains (tyrosine kinase [TK] and Immunoglobulin [Ig]-like).
- Engineering ICC cells to express specific FGFR2 fusions and assessing sensitivity to FGFR kinase inhibitors, including pathway activity analysis (MAPK/ERK, AKT/PI3K).
Main Results:
- Nine FGFR2 translocations (5.2%) were identified in ICC, predominantly in mass-forming, small bile duct types.
- FGFR2 fusions were classified into classical (retaining TK and Ig-like domains), sub-classical (retaining TK only), and non-classical (lacking both).
- Cells with classical and sub-classical FGFR2 fusions showed sensitivity to FGFR inhibitors, with suppressed MAPK/ERK and AKT/PI3K signaling; kinase-deficient mutants lost sensitivity.
Conclusions:
- The type and breakpoint of FGFR2 fusions are crucial determinants of therapeutic sensitivity in ICC.
- Classical and sub-classical FGFR2 fusions represent actionable targets for FGFR kinase inhibitors in ICC.
- Determining FGFR2 fusion status is essential for guiding targeted treatment strategies in the small bile duct subtype of ICC.
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