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

February 12, 2024

Stephan Spahn # 1, Fabian Kleinhenz # 2, Ekaterina Shevchenko 3 4, Aaron Stahl 5, Yvonne Rasen 2, Christine Geisler 2, Kristina Ruhm 6, Marion Klaumuenzer 7, Thales Kronenberger 3 4, Stefan A Laufer 3 4 8, Holly Sundberg-Malek 6, Khac Cuong Bui 2, Marius Horger 9, Saskia Biskup 7, Klaus Schulze-Osthoff 8 10 11, Markus Templin 5, Nisar P Malek 2 6 8 11 12, Antti Poso 3 4 8 13, Michael Bitzer 14 15 16 17

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.

  1. Department of Internal Medicine I, University Hospital Tuebingen, 72076, Tuebingen, Germany. stephan.spahn@med.uni-tuebingen.de.
  2. Department of Internal Medicine I, University Hospital Tuebingen, 72076, Tuebingen, Germany.
  3. Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard-Karls-University, 72076, Tuebingen, Germany.
  4. Tuebingen Center for Academic Drug Discovery & Development (TüCAD2), 72076, Tuebingen, Germany.
  5. NMI Natural and Medical Sciences Institute at the University of Tuebingen, 72770, Reutlingen, Germany.
  6. Center for Personalized Medicine, Eberhard-Karls University, 72076, Tuebingen, Germany.
  7. CeGaT GmbH and Praxis für Humangenetik, 72076, Tuebingen, Germany.
  8. Cluster of Excellence, Image Guided and Functionally Instructed Tumor Therapies, Eberhard-Karls University, 72076, Tuebingen, Germany.
  9. Department of Diagnostic and Interventional Radiology, Eberhard-Karls University, 72076, Tuebingen, Germany.
  10. Department of Molecular Medicine, Interfaculty Institute for Biochemistry, Eberhard-Karls University, 72076, Tuebingen, Germany.
  11. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
  12. M3-Research Center for Malignome, Metabolome and Microbiome, Eberhard-Karls University, 72076, Tuebingen, Germany.
  13. School of Pharmacy, University of Eastern Finland, 70210, Kuopio, Finland.
  14. Department of Internal Medicine I, University Hospital Tuebingen, 72076, Tuebingen, Germany. michael.bitzer@uni-tuebingen.de.
  15. Center for Personalized Medicine, Eberhard-Karls University, 72076, Tuebingen, Germany. michael.bitzer@uni-tuebingen.de.
  16. Cluster of Excellence, Image Guided and Functionally Instructed Tumor Therapies, Eberhard-Karls University, 72076, Tuebingen, Germany. michael.bitzer@uni-tuebingen.de.
  17. M3-Research Center for Malignome, Metabolome and Microbiome, Eberhard-Karls University, 72076, Tuebingen, Germany. michael.bitzer@uni-tuebingen.de.

# Contributed equally.