Masahito Ogasawara1, Yutaka Nakamura2, Naoto Morikawa3, Hiroo Nitanai3, Satoshi Moriguchi3, Ryosuke Chiba3, Heisuke Saito3, Mika Ohta4, Tatsuo Tanita5, Tamotsu Sugai6, Kazutaka Maeyama1, Kohei Yamauchi3, Yutaka Takaoka4. 1. Department of Pharmacology, Ehime University Graduate School of Medicine, Matsuyama, 7910295, Japan. 2. Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, 0208505, Japan. ICB75097@nifty.com. 3. Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, 0208505, Japan. 4. Division of Medical Informatics and Bioinformatics, Kobe University Graduate School of Medicine, Kobe, 6500017, Japan. 5. Department of Thoracic Surgery, Iwate Medical University School of Medicine, Morioka, 0208505, Japan. 6. Department of Molecular Diagnostic Pathology, Iwate Medical University School of Medicine, Morioka, 0208505, Japan.
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.
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 EGFRdelE746. 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.