title: Evaluation of two phosphorylation sites improves the prognostic significance of Akt activation in non-small-cell lung cancer tumors.
abstract: OBJECTIVE
  Akt is a serine/threonine kinase that has been implicated in lung tumorigenesis and lung cancer therapeutic resistance. Full activation of Akt requires two phosphorylation events, but only one site of phosphorylation (S473) has been evaluated thus far in clinical non-small-cell lung cancer (NSCLC) specimens, which has resulted in conflicting results regarding the prognostic significance of Akt activation in NSCLC. In this study, we sought to determine whether evaluation of Akt phosphorylation at T308 would improve prognostic accuracy.
  
  
  METHODS
  Phosphospecific antibodies against T308 and S473 were validated and used in an immunohistochemical analysis of tissue microarray slides containing NSCLC specimens (n = 300) and surrounding lung tissue specimens (n = 100).
  
  
  RESULTS
  Phosphorylation of either S473 or T308 was positive in most NSCSLC specimens, but was detected rarely in surrounding normal tissues. When Akt activation was defined by using both sites of phosphorylation, Akt activation was specific for NSCLC tumors versus surrounding tissue (73.4% v 0%; P < .05), was higher in adenocarcinoma than in squamous cell carcinoma (78.1% v 68.5%; P = .040), and was associated with shorter overall survival for all stages of disease (log-rank P = .041). In multivariate analyses, increased phosphorylation of T308 alone was a poor prognostic factor for stage I patients or for tumors < 5 cm (log-rank P = .011 and P = .015, respectively).
  
  
  CONCLUSIONS
  These results suggest that monitoring phosphorylation of Akt at T308 improves the assessment of Akt activation, and show that Akt activation is a poor prognostic factor for all stages of NSCLC.
authors.affiliation: Cancer Therapeutics Branch, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Junji
authors.initials: J
authors.lastname: Tsurutani
authors.forename: Junya
authors.initials: J
authors.lastname: Fukuoka
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tsurutani
authors.forename: Joanna H
authors.initials: JH
authors.lastname: Shih
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.forename: William D
authors.initials: WD
authors.lastname: Travis
authors.forename: Jin
authors.initials: J
authors.lastname: Jen
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Dennis
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000401:mortality; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D051057:Proto-Oncogene Proteins c-akt