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Updated: Mar 15, 2026
Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
Published on: September 30, 2019
Biophysical characterization of drug-resistant mutants of fibroblast growth factor receptor 1
Kaito Yoza1, Rika Himeno1, Shinjiro Amano2
1Department of Analytical and Biophysical Chemistry, School of Pharmacy, Kumamoto University, Kumamoto, 862-0973, Japan.
Abstract:
Over-expression and aberrant activation of tyrosine kinases occur frequently in human cancers. Various tyrosine kinase inhibitors (TKIs) are under clinical use, but acquisition of resistance to these drugs is a major problem. Here, we studied the interaction between two drug-resistant mutants of fibroblast growth factor receptor 1 (FGFR1), N546K and V561M, and four ATP-competitive inhibitors, ponatinib, dovitinib, PD173074 and BGJ-398. Among these protein-drug systems, the only marked reduction in affinity was that of PD173074 for the V561M mutant. We also examined the interaction of these FGFR1 variants to AMP-PNP, a nonhydrolyzable analogue of ATP, and showed that N546K showed increased affinity for the ATP analogue as compared with the wild type. These findings will help to clarify the mechanism of drug resistance in mutant tyrosine kinases.
Insights
Drug resistance in cancer tyrosine kinases is a challenge. This study reveals how specific mutations in fibroblast growth factor receptor 1 (FGFR1) affect inhibitor binding, offering insights into overcoming resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Tyrosine kinases are frequently over-expressed and aberrantly activated in human cancers.
- Tyrosine kinase inhibitors (TKIs) are vital in cancer treatment, but drug resistance is a significant clinical hurdle.
Purpose of the Study:
- To investigate the interaction between drug-resistant fibroblast growth factor receptor 1 (FGFR1) mutants (N546K and V561M) and four ATP-competitive inhibitors.
- To elucidate the molecular mechanisms underlying TKI resistance in mutant FGFR1.
Main Methods:
- Studied the binding affinities of FGFR1 mutants (N546K, V561M) with four TKIs: ponatinib, dovitinib, PD173074, and BGJ398.
- Assessed the interaction of FGFR1 variants with AMP-PNP, a non-hydrolyzable ATP analog.
Main Results:
- A marked reduction in binding affinity was observed for PD173074 with the V561M FGFR1 mutant.
- The N546K FGFR1 mutant exhibited increased affinity for the ATP analog (AMP-PNP) compared to the wild-type receptor.
Conclusions:
- Specific mutations in FGFR1 can alter drug-target interactions, contributing to TKI resistance.
- Understanding these altered interactions is crucial for developing strategies to overcome drug resistance in tyrosine kinase-driven cancers.
