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

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.

Targeting FGFR for cancer therapy

“…In vitro experiments have provided evidence that lenvatinib effectively suppresses the proliferation signaling pathway of overexpressed VEGFR and FGFR in cancer cells [ 156 ]. Interestingly, lenvatinib offers a promising therapeutic option for FGFR 2-driven CCA, especially in cases involving insurmountable adverse effects to selective Tkis or acquired kinase mutations [ 157 ]. A Phase III clinical trial showed that lenvatinib was not inferior to sorafenib in patients with previously untreated advanced HCC (median survival time: 13.6 vs. 12.3 months), in contrast to sorafenib, lenvatinib exhibited substantial enhancements across all secondary endpoints, including a greater ORR, extended PFS, and increased time to progression (TTP) [ 158 ].…”