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Ref Type Journal Article
PMID (38346946)
Authors Spahn S, Kleinhenz F, Shevchenko E, Stahl A, Rasen Y, Geisler C, Ruhm K, Klaumuenzer M, Kronenberger T, Laufer SA, Sundberg-Malek H, Bui KC, Horger M, Biskup S, Schulze-Osthoff K, Templin M, Malek NP, Poso A, Bitzer M
Title The molecular interaction pattern of lenvatinib enables inhibition of wild-type or kinase-mutated FGFR2-driven cholangiocarcinoma.
Journal Vol Issue Date Pages Journal Short Title
Nature communications 15 1 2024 Feb 12 1287 Nat Commun
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 S372C cholangiocarcinoma predicted - sensitive Lenvatinib Case Reports/Case Series Actionable In a clinical case study, Lenvima (lenvatinib) treatment resulted in a partial response in a patient with cholangiocarcinoma harboring FGFR2 S372C (PMID: 38346946). 38346946