title: Epidermal growth factor receptor mutation in combination with expression of MIG6 alters gefitinib sensitivity.
abstract: BACKGROUND
  Epidermal growth factor receptor (EGFR) signaling plays an important role in the regulation of cell proliferation, survival, metastasis, and invasion in various tumors. Earlier studies showed that the EGFR is frequently overexpressed in non-small-cell lung cancer (NSCLC) and EGFR mutations at specific amino acid residues in the kinase domain induce altered responsiveness to gefitinib, a small molecule EGFR tyrosine kinase inhibitor. However, the mechanism underlying the drug response modulated by EGFR mutation is still largely unknown. To elucidate drug response in EGFR signal transduction pathway in which complex dynamics of multiple molecules involved, a systematic approach is necessary. In this paper, we performed experimental and computational analyses to clarify the underlying mechanism of EGFR signaling and cell-specific gefitinib responsiveness in three H1299-derived NSCLC cell lines; H1299 wild type (H1299WT), H1299 with an overexpressed wild type EGFR (H1299EGFR-WT), and H1299 with an overexpressed mutant EGFR L858R (H1299L858R; gefitinib sensitive mutant).
  
  
  RESULTS
  We predicted and experimentally verified that Mig6, which is a known negative regulator of EGFR and specifically expressed in H1299L858R cells, synergized with gefitinib to suppress cellular growth. Computational analyses indicated that this inhibitory effect is amplified at the phosphorylation/dephosphorylation steps of MEK and ERK.
  
  
  CONCLUSIONS
  Thus, we showed that L858R receptor mutation in combination with expression of its negative regulator, Mig6, alters signaling outcomes and results in variable drug sensitivity.
authors.affiliation: Laboratory for Cellular Systems Modeling, RIKEN Research Center for Allergy and Immunology (RCAI), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Naruo
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagashima
authors.forename: Ryoko
authors.initials: R
authors.lastname: Ushikoshi-Nakayama
authors.forename: Yuko
authors.initials: Y
authors.lastname: Saeki
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakakuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Naka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Shih-Feng
authors.initials: SF
authors.lastname: Tsai
authors.forename: Mariko
authors.initials: M
authors.lastname: Okada-Hatakeyama
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019295:Computational Biology; D017931:DNA Primers / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology; D000077156:Gefitinib; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; C484017:ERRFI1 protein, human; D011799:Quinazolines; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors; D000077156:Gefitinib