Related Experiment Video
Updated: Nov 23, 2025
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Extensive functional evaluation of exon 20 insertion mutations of EGFR
Takeshi Hirose1, Masachika Ikegami2, Makoto Endo3
1Division of Cellular Signaling, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan; Department of Orthopaedic Surgery, Graduate School of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Objectives:
Exon 20 insertion mutations of epidermal growth factor receptor (EGFR) have been identified as oncogenic mutations in general; however, the functional relevance of each remains largely uninvestigated. Herein, we comprehensively assessed the functional significance of insertion mutations of EGFR exon 20.
Materials And Methods:
The transforming potential and drug sensitivities of 25 EGFR recurrent mutants, including twenty-one exon 20 insertions, were evaluated using the mixed-all-nominated-in-one method.
Results:
The sensitivity of EGFR exon 20 insertions to EGFR tyrosine kinase inhibitors (TKIs) was generally lower than that of the L858R mutation or exon 19 deletions. The results were also confirmed through an in vivo drug test. All of the exon 20 insertions were resistant to gefitinib and afatinib, whereas several mutants were sensitive to osimertinib. EGFR exon 20 insertions exhibited relatively good responses to poziotinib and mobocertinib.
Conclusions:
EGFR exon 20 insertions were shown to have different degrees of sensitivity to EGFR TKIs. This extensive assessment of EGFR exon 20 insertions may provide a fundamental database for aiding in a customized mode of therapy for cancers having insertional mutations within exon 20 of EGFR, although the clinical impact of preclinical data should be validated by clinical evidence in the future.
Insights
EGFR exon 20 insertion mutations show varied sensitivity to tyrosine kinase inhibitors. While generally resistant to first-generation inhibitors, some mutations respond to newer drugs like osimertinib, poziotinib, and mobocertinib.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene are recognized as oncogenic drivers.
- The specific functional impact and drug sensitivity profiles of most EGFR exon 20 insertions remain largely uncharacterized.
Purpose of the Study:
- To comprehensively evaluate the functional significance and drug sensitivities of various EGFR exon 20 insertion mutations.
- To establish a foundational understanding for personalized therapeutic strategies in cancers with these mutations.
Main Methods:
- Utilized the mixed-all-nominated-in-one method to assess the transforming potential and drug sensitivities of 25 recurrent EGFR mutants, including 21 exon 20 insertions.
- Conducted in vivo drug testing to validate findings on drug sensitivities.
Main Results:
- EGFR exon 20 insertions demonstrated generally lower sensitivity to EGFR tyrosine kinase inhibitors (TKIs) compared to L858R mutations or exon 19 deletions.
- All tested exon 20 insertions were resistant to gefitinib and afatinib; however, several showed sensitivity to osimertinib, poziotinib, and mobocertinib.
Conclusions:
- EGFR exon 20 insertions exhibit differential sensitivity to various EGFR TKIs.
- This research provides a crucial database for developing customized therapies for cancers harboring EGFR exon 20 insertional mutations, pending clinical validation.
More Related Videos
10:57Visualizing Genetic Variants, Short Targets, and Point Mutations in the Morphological Tissue Context with an RNA In Situ Hybridization Assay
Published on: August 14, 2018
11:15Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
