Targeting extracellular and juxtamembrane FGFR2 mutations in chemotherapy-refractory cholangiocarcinoma

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• Intrahepatic cholangiocarcinoma (iCCA) is a potential target for precision medicine, particularly with FGFR2 gene fusions.
• FGFR2 mutations, besides fusions, are found in iCCA but their functional impact remains largely unknown.
• Predicting the functional consequences of FGFR2 alterations is crucial for guiding treatment decisions in molecular tumor boards (MTBs).

Purpose of the Study:

• To investigate the functional significance of specific FGFR2 mutations in intrahepatic cholangiocarcinoma.
• To establish an approach for characterizing FGFR2 mutations to guide precision medicine treatment.
• To evaluate the efficacy of FGFR-inhibiting tyrosine kinase inhibitors in iCCA patients with specific FGFR2 mutations.

Main Methods:

• In silico investigation of FGFR2 alterations.
• Immunohistochemistry and transcriptome analysis to identify activated FGFR2 downstream targets in tumor specimens.
• Molecular tumor board (MTB) review and treatment recommendation.

Main Results:

• Two iCCA patients with extracellular and juxtamembrane FGFR2 mutations were identified.
• Treatment with an FGFR-inhibiting tyrosine kinase inhibitor resulted in a rapid, detectable, and prolonged partial response in both patients.
• The study demonstrated a successful approach to characterize FGFR2 mutations for patient selection.

Conclusions:

• Characterizing FGFR2 mutations in iCCA is essential for effective patient selection for FGFR-inhibiting therapies.
• This approach can guide the successful application of FGFR-inhibiting drugs in iCCA.
• The findings support the role of precision medicine in treating intrahepatic cholangiocarcinoma based on specific genetic alterations.