title: Comprehensive analysis of EGFR signaling pathways in Japanese patients with non-small cell lung cancer.
abstract: OBJECTIVE
  Translational approach is essentially needed to return the achievement of basic researches to oncological practice. The molecular associations among EGFR mutation and the components of EGFR signaling pathways have been extensively studied in laboratory experiments, although were still controversial. Moreover, the impact of downstream signaling of EGFR on clinical features in patients with non-small cell lung cancer (NSCLC) remains undetermined.
  
  
  METHODS
  A total of 93 surgically resected NSCLC patients were recruited the study. EGFR mutation status was analyzed by direct sequence method. The protein expression levels of EGFR, phosphorylated EGFR (pEGFR), phosphorylated Akt (pAkt), and phosphorylated MAPK (pMAPK) were determined by immunohistochemistry.
  
  
  RESULTS
  There were 37 (40%) patients whose tumor harboring EGFR mutations (1 in exon 18, 22 in exon 19, and 14 in exon 21). Protein expression of EGFR, pEGFR, pAkt, and pMAPK was detected in 61 (66%), 27 (29%), 58 (62%), and 41 (44%) patients, respectively. The expression of pAkt was significantly associated with female gender and never-smoking history, and it was frequently upregulated in tumors harboring EGFR mutations (p<0.05, each). Phosphorylation of EGFR was closely correlated with the EGFR protein expression (p<0.05), but not with the EGFR mutations. In regard to patient survival, none of the molecular biomarkers was predictive for survival after surgical resection, but pMAPK expression was predictive for poor prognosis after gefitinib treatment in patients with postoperative recurrence (p<0.05), suggesting the strong linkage between pMAPK expression and survival benefit from gefitinib.
  
  
  CONCLUSIONS
  Our result could provide new insight into MAP kinase signaling when we treat NSCLC patients with gefitinib.
authors.affiliation: Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Hosokawa
authors.forename: Shinichi
authors.initials: S
authors.lastname: Toyooka
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Masaki
authors.initials: M
authors.lastname: Tokumo
authors.forename: Junichi
authors.initials: J
authors.lastname: Soh
authors.forename: Nagio
authors.initials: N
authors.lastname: Takigawa
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Hotta
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshino
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
authors.forename: Mitsune
authors.initials: M
authors.lastname: Tanimoto
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kiura
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000401:mortality / Q000628:therapy*; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D015870:Gene Expression; D018773:Genes, erbB-1 / Q000187:drug effects; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000401:mortality / Q000628:therapy*; D008297:Male; D009154:Mutation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib