The molecular interaction pattern of lenvatinib enables inhibition of wild-type or kinase-mutated FGFR2-driven cholangiocarcinoma

February 12, 2024

Stephan Spahn # 1, Fabian Kleinhenz # 2, Ekaterina Shevchenko 3 4, Aaron Stahl 5, Yvonne Rasen 2, Christine Geisler 2, Kristina Ruhm 6, Marion Klaumuenzer 7, Thales Kronenberger 3 4, Stefan A Laufer 3 4 8, Holly Sundberg-Malek 6, Khac Cuong Bui 2, Marius Horger 9, Saskia Biskup 7, Klaus Schulze-Osthoff 8 10 11, Markus Templin 5, Nisar P Malek 2 6 8 11 12, Antti Poso 3 4 8 13, Michael Bitzer 14 15 16 17


Fibroblast growth factor receptor (FGFR)-2 can be inhibited by FGFR-selective or non-selective tyrosine kinase inhibitors (TKIs). Selective TKIs are approved for cholangiocarcinoma (CCA) with FGFR2 fusions; however, their application is limited by a characteristic pattern of adverse events or evocation of kinase domain mutations. A comprehensive characterization of a patient cohort treated with the non-selective TKI lenvatinib reveals promising efficacy in FGFR2-driven CCA. In a bed-to-bench approach, we investigate FGFR2 fusion proteins bearing critical tumor-relevant point mutations. These mutations confer growth advantage of tumor cells and increased resistance to selective TKIs but remain intriguingly sensitive to lenvatinib. In line with clinical observations, in-silico analyses reveal a more favorable interaction pattern of lenvatinib with FGFR2, including an increased flexibility and ligand efficacy, compared to FGFR-selective TKIs. Finally, the treatment of a patient with progressive disease and a newly developed kinase mutation during therapy with a selective inhibitor results in a striking response to lenvatinib. Our in vitro, in silico, and clinical data suggest that lenvatinib is a promising treatment option for FGFR2-driven CCA, especially when insurmountable adverse reactions of selective TKIs or acquired kinase mutations occur.