title: Analysis of a single-codon E746 deletion in exon 19 of the epidermal growth factor receptor.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Our study revealed biological, structural, and probably clinical features of the delE746 form of EGFR.
authors.affiliation: Department of Pharmacology, Ehime University Graduate School of Medicine, Matsuyama, 7910295, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Ogasawara
authors.affiliation: 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.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, 0208505, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Morikawa
authors.affiliation: Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, 0208505, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Nitanai
authors.affiliation: Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, 0208505, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Moriguchi
authors.affiliation: Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, 0208505, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Chiba
authors.affiliation: Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, 0208505, Japan.
authors.forename: Heisuke
authors.initials: H
authors.lastname: Saito
authors.affiliation: Division of Medical Informatics and Bioinformatics, Kobe University Graduate School of Medicine, Kobe, 6500017, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Ohta
authors.affiliation: Department of Thoracic Surgery, Iwate Medical University School of Medicine, Morioka, 0208505, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Tanita
authors.affiliation: Department of Molecular Diagnostic Pathology, Iwate Medical University School of Medicine, Morioka, 0208505, Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Sugai
authors.affiliation: Department of Pharmacology, Ehime University Graduate School of Medicine, Matsuyama, 7910295, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Maeyama
authors.affiliation: Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka, 0208505, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Yamauchi
authors.affiliation: Division of Medical Informatics and Bioinformatics, Kobe University Graduate School of Medicine, Kobe, 6500017, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takaoka
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003062:Codon; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005091:Exons; D000077156:Gefitinib; D017353:Gene Deletion; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D051379:Mice; D062105:Molecular Docking Simulation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D003062:Codon; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Epidermal growth factor receptor; Exon 19; Gefitinib; Single-codon deletion; Tyrosine kinase inhibitor