title: V843I, a lung cancer predisposing EGFR mutation, is responsible for resistance to EGFR tyrosine kinase inhibitors.
abstract: BACKGROUND
  We previously demonstrated that a family predisposed to lung cancer harbored a V843I substitution in the epidermal growth factor receptor (EGFR) protein. We report here the further characterization of this mutant EGFR protein in the context of tumorigenicity and resistance to tyrosine kinase inhibitors (TKIs) of EGFR activity.
  
  
  METHODS
  Phosphorylation of EGFR and downstream signaling proteins of lung adenocarcinoma cell lines with EGFR mutations was assayed by flow cytometry. Susceptibility to TKIs of these cell lines, with or without suppression of mutant EGFR expression by small inhibitory RNA (siRNA), was investigated using a cellular viability assay. Furthermore, protein modeling was used to predict TKI binding to EGFR protein carrying the V843I mutation.
  
  
  RESULTS
  Phosphorylation of EGFR and downstream signaling proteins was elevated upon transfection with an EGFR gene with the V843I. Although the cell line with V843I + L858R demonstrated resistance to EGFR-TKIs, the cells became susceptible to TKIs upon incubation with siRNA specific for the V843I allele. The structural analysis suggested that TKI binding to EGFR would be sterically hindered by Arg841 in the double-mutant (V843I + L858R) EGFR.
  
  
  CONCLUSIONS
  The V843I mutation contributes to tumorigenesis by promoting phosphorylation of EGFR and its downstream signaling proteins. This mutation also appears to provide resistance to EGFR-TKIs through structural modification of EGFR. These features are comparable with those in EGFR T790M mutation, suggesting that cases with germ-line V843I or T790M mutations could be categorized as a class of familial lung cancer syndrome with resistance to EGFR-TKIs.
authors: *Department of Laboratory Medicine; †Department of Pathology, Kyorin University School of Medicine, Tokyo; ‡Chemical Resources Laboratory, Tokyo Institute of Technology, Kanagawa; §Department of Orthopedic Surgery; and ‖Department of Respiratory Medicine, Kyorin University School of Medicine, Tokyo, Japan.
authors: Satsuki
authors: S
authors: Matsushima
authors: Kouki
authors: K
authors: Ohtsuka
authors: Hiroaki
authors: H
authors: Ohnishi
authors: Masachika
authors: M
authors: Fujiwara
authors: Hiroyuki
authors: H
authors: Nakamura
authors: Takeshi
authors: T
authors: Morii
authors: Tomonori
authors: T
authors: Kishino
authors: Hajime
authors: H
authors: Goto
authors: Takashi
authors: T
authors: Watanabe
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D017209:Apoptosis; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D015398:Signal Transduction
chemical_list: D004273:DNA, Neoplasm; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors