The molecular interaction pattern of lenvatinib enables inhibition of wild-type or kinase-mutated FGFR2-driven cholangiocarcinoma
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Updated: Jul 3, 2025
A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
Stephan Spahn1, Fabian Kleinhenz2, Ekaterina Shevchenko3,4
1Department of Internal Medicine I, University Hospital Tuebingen, 72076, Tuebingen, Germany. stephan.spahn@med.uni-tuebingen.de.
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.
Insights
Lenvatinib, a non-selective tyrosine kinase inhibitor (TKI), shows promise for treating cholangiocarcinoma (CCA) with FGFR2 fusions, especially when selective TKIs cause adverse events or resistance mutations. This TKI remains effective against resistant FGFR2 mutations, offering a viable treatment option.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Fibroblast growth factor receptor (FGFR)-2 alterations drive cholangiocarcinoma (CCA) growth.
- Selective tyrosine kinase inhibitors (TKIs) targeting FGFR2 are approved for CCA but have limitations.
- Adverse events and acquired resistance mutations limit the efficacy of selective FGFR2 inhibitors.
Purpose of the Study:
- To evaluate the efficacy of the non-selective TKI lenvatinib in FGFR2-driven CCA.
- To investigate the impact of tumor-relevant point mutations on FGFR2 sensitivity to TKIs.
- To compare the interaction patterns of lenvatinib and selective TKIs with FGFR2.
Main Methods:
- Patient cohort characterization treated with lenvatinib.
- In vitro studies of FGFR2 fusion proteins with point mutations.
- In silico analyses of TKI-FGFR2 interactions.
- Clinical case study of a patient with acquired resistance.
Main Results:
- Lenvatinib demonstrated promising efficacy in FGFR2-driven CCA patients.
- FGFR2 mutations conferring resistance to selective TKIs remained sensitive to lenvatinib.
- In silico analyses revealed lenvatinib's favorable binding profile with FGFR2.
- A patient with acquired resistance showed a striking response to lenvatinib.
Conclusions:
- Lenvatinib is a potential therapeutic option for FGFR2-driven CCA.
- Lenvatinib overcomes resistance mechanisms associated with selective TKI therapy.
- Lenvatinib offers a valuable alternative when selective inhibitors are not tolerated or become ineffective due to mutations.
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