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

Stephan Spahn (), Fabian Kleinhenz, Ekaterina Shevchenko, Aaron Stahl, Yvonne Rasen, Christine Geisler, Kristina Ruhm, Marion Klaumuenzer, Thales Kronenberger, Stefan A. Laufer, Holly Sundberg-Malek, Khac Cuong Bui, Marius Horger, Saskia Biskup, Klaus Schulze-Osthoff, Markus Templin, Nisar P. Malek, Antti Poso and Michael Bitzer ()
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Stephan Spahn: University Hospital Tuebingen
Fabian Kleinhenz: University Hospital Tuebingen
Ekaterina Shevchenko: Eberhard-Karls-University
Aaron Stahl: NMI Natural and Medical Sciences Institute at the University of Tuebingen
Yvonne Rasen: University Hospital Tuebingen
Christine Geisler: University Hospital Tuebingen
Kristina Ruhm: Eberhard-Karls University
Marion Klaumuenzer: CeGaT GmbH and Praxis für Humangenetik
Thales Kronenberger: Eberhard-Karls-University
Stefan A. Laufer: Eberhard-Karls-University
Holly Sundberg-Malek: Eberhard-Karls University
Khac Cuong Bui: University Hospital Tuebingen
Marius Horger: Eberhard-Karls University
Saskia Biskup: CeGaT GmbH and Praxis für Humangenetik
Klaus Schulze-Osthoff: Eberhard-Karls University
Markus Templin: NMI Natural and Medical Sciences Institute at the University of Tuebingen
Nisar P. Malek: University Hospital Tuebingen
Antti Poso: Eberhard-Karls-University
Michael Bitzer: University Hospital Tuebingen

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-45247-6

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