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Updated: Mar 23, 2026
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Analysis of a single-codon E746 deletion in exon 19 of the epidermal growth factor receptor
Masahito Ogasawara1, Yutaka Nakamura2, Naoto Morikawa3
1Department of Pharmacology, Ehime University Graduate School of Medicine, Matsuyama, 7910295, Japan.
Purpose:
Epidermal growth factor receptor (EGFR) gene mutations are the most established genomic biomarkers for the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). The most frequent deletion in exon 19 is delE746_750, followed by del747_753insS and del747_750insP. Since investigations of delE746 have not been reported previously, it is unclear if delE746 conveys sensitivity to TKI effect of TKI on EGFR delE746. The objective was to characterize delE746 of the EGFR gene and to explore the effects of TKIs on the delE746.
Methods:
We assessed the ability of gefitinib to inhibit phosphorylation of clonal L929 cell lines expressing EGFR with delE746. 3-D structures of the EGFR proteins were also used to investigate the interaction with gefitinib.
Results:
The delE746 mutant EGFR-expressing cells exhibited gefitinib-sensitive autophosphorylation, which altered the structure of the EGFR and increased the instances of docking during docking simulations of gefitinib with the EGFR-TK. This mutant revealed that it exhibited molecular conformation alterations, and more frequent binding with gefitinib compared to wild-type EGFR. We administered EGFR-TKI, gefitinib to a Japanese woman with lung cancer that contained delE746. The patient achieved partial response after a 5 month of treatment with gefitinib.
Conclusion:
Our study revealed biological, structural, and probably clinical features of the delE746 form of EGFR.
Insights
This study characterizes the delE746 mutation in the epidermal growth factor receptor (EGFR) gene. Gefitinib demonstrated sensitivity to this mutation, showing potential clinical efficacy in lung cancer patients.
Area of Science:
- Genomics
- Molecular Biology
- Oncology
Background:
- Epidermal growth factor receptor (EGFR) gene mutations are key biomarkers for EGFR tyrosine kinase inhibitor (EGFR-TKI) efficacy.
- Common exon 19 deletions include delE746_750, del747_753insS, and del747_750insP.
- The specific impact of the delE746 mutation on TKI sensitivity remained uninvestigated.
Purpose of the Study:
- To characterize the delE746 mutation of the EGFR gene.
- To investigate the effects of TKIs on the delE746 mutation.
Main Methods:
- Assessed gefitinib's ability to inhibit phosphorylation in cell lines expressing EGFR with delE746.
- Utilized 3-D protein structures to investigate gefitinib interaction with EGFR.
Main Results:
- EGFR delE746 mutant cells showed gefitinib-sensitive autophosphorylation and altered EGFR structure.
- Docking simulations revealed increased gefitinib binding to the delE746 mutant compared to wild-type EGFR.
- A lung cancer patient with delE746 achieved partial response after 5 months of gefitinib treatment.
Conclusions:
- The study elucidated biological, structural, and potential clinical features of the EGFR delE746 mutation.
- EGFR delE746 is a potentially actionable mutation for EGFR-TKI therapy.
