Related Experiment Video
Updated: Oct 28, 2025
A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors
Published on: March 15, 2016
Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer
Ikuko Takeda Nakamura1,2, Shinji Kohsaka3, Masachika Ikegami1,4
1Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan.
Abstract:
Various genetic alterations of the fibroblast growth factor receptor (FGFR) family have been detected across a wide range of cancers. However, inhibition of FGFR signaling by kinase inhibitors demonstrated limited clinical effectiveness. Herein, we evaluated the transforming activity and sensitivity of 160 nonsynonymous FGFR mutations and ten fusion genes to seven FGFR tyrosine kinase inhibitors (TKI) using the mixed-all-nominated-in-one (MANO) method, a high-throughput functional assay. The oncogenicity of 71 mutants was newly discovered in this study. The FGFR TKIs showed anti-proliferative activities against the wild-type FGFRs and their fusions, while several hotspot mutants were relatively resistant to those TKIs. The drug sensitivities assessed with the MANO method were well concordant with those evaluated using in vitro and in vivo assays. Comprehensive analysis of published FGFR structures revealed a possible mechanism through which oncogenic FGFR mutations reduce sensitivity to TKIs. It was further revealed that recurrent compound mutations within FGFRs affect the transforming potential and TKI-sensitivity of corresponding kinases. In conclusion, our study suggests the importance of selecting suitable inhibitors against individual FGFR variants. Moreover, it reveals the necessity to develop next-generation FGFR inhibitors, which are effective against all oncogenic FGFR variants.
Insights
Fibroblast growth factor receptor (FGFR) mutations drive cancer, but current tyrosine kinase inhibitors (TKIs) show limited effectiveness against many variants. New research highlights the need for tailored inhibitors and next-generation drugs to overcome resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Fibroblast growth factor receptor (FGFR) genetic alterations are prevalent in various cancers.
- Current fibroblast growth factor receptor tyrosine kinase inhibitors (FGFR TKIs) exhibit limited clinical efficacy against FGFR-driven malignancies.
Purpose of the Study:
- To comprehensively evaluate the oncogenic activity and drug sensitivity of numerous FGFR mutations and fusions.
- To investigate the mechanisms underlying resistance to FGFR TKIs.
Main Methods:
- Utilized the mixed-all-nominated-in-one (MANO) assay, a high-throughput functional screening method.
- Assessed 160 nonsynonymous FGFR mutations and 10 fusion genes against 7 FGFR TKIs.
- Analyzed FGFR structural data and compound mutation effects.
Main Results:
- Identified 71 novel oncogenic FGFR mutations.
- Demonstrated that while FGFR TKIs inhibit wild-type and fusion variants, several hotspot mutants display resistance.
- Observed concordance between MANO assay results and traditional in vitro/in vivo assays.
- Elucidated potential mechanisms of TKI resistance linked to FGFR mutation structures and compound mutations.
Conclusions:
- Emphasizes the critical need for personalized TKI selection based on specific FGFR variants.
- Underscores the necessity for developing next-generation FGFR inhibitors effective against a broader spectrum of oncogenic FGFR alterations.
