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04.04.2016 | Original Article

Analysis of a single-codon E746 deletion in exon 19 of the epidermal growth factor receptor

verfasst von: Masahito Ogasawara, Yutaka Nakamura, Naoto Morikawa, Hiroo Nitanai, Satoshi Moriguchi, Ryosuke Chiba, Heisuke Saito, Mika Ohta, Tatsuo Tanita, Tamotsu Sugai, Kazutaka Maeyama, Kohei Yamauchi, Yutaka Takaoka

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 5/2016

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Abstract

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.

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Titel: Analysis of a single-codon E746 deletion in exon 19 of the epidermal growth factor receptor
verfasst von: Masahito Ogasawara
Yutaka Nakamura
Naoto Morikawa
Hiroo Nitanai
Satoshi Moriguchi
Ryosuke Chiba
Heisuke Saito
Mika Ohta
Tatsuo Tanita
Tamotsu Sugai
Kazutaka Maeyama
Kohei Yamauchi
Yutaka Takaoka
Publikationsdatum: 04.04.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 5/2016
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-016-3021-y

Springer Medizin

Analysis of a single-codon E746 deletion in exon 19 of the epidermal growth factor receptor