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

• Published in: Nature communications Vol. 15; no. 1; p. 1287
• Main Authors: Spahn, Stephan, Kleinhenz, Fabian, Shevchenko, Ekaterina, Stahl, Aaron, Rasen, Yvonne, Geisler, Christine, Ruhm, Kristina, Klaumuenzer, Marion, Kronenberger, Thales, Laufer, Stefan A., Sundberg-Malek, Holly, Bui, Khac Cuong, Horger, Marius, Biskup, Saskia, Schulze-Osthoff, Klaus, Templin, Markus, Malek, Nisar P., Poso, Antti, Bitzer, Michael
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.02.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 119/118; 13/106; 13/109; 13/44; 38/70; 38/79; 692/308/575; 692/4028/67/1059/2326; 692/4028/67/1059/602; 692/4028/67/1504/1329; 82/80; 96/95; Cholangiocarcinoma; Effectiveness; Enzyme inhibitors; Fibroblast growth factor receptor 2; Fibroblast growth factor receptors; Fibroblasts; Growth factors; Health services; Humanities and Social Sciences; Inhibitors; Kinases; Molecular interactions; multidisciplinary; Mutation; Patients; Receptors; Science; Science (multidisciplinary); Side effects; Tumor cells; Tumors; Tyrosine; Tyrosine kinase inhibitors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45247-6

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. The application of fibroblast growth factor receptor (FGFR)−2 selective tyrosine kinase inhibitors (TKIs) in cholangiocarcinoma (CCA) with FGFR2 fusions has been reported to lead to mutations in the kinase domain of FGFR2. Here, the authors report that non-selective TKI, lenvatinib may be an alternative in case of insurmountable side effects to specific FGFR inhibitors or to overcome and delay the development of resistance mediating FGFR2 mutations.