Evaluation of two phosphorylation sites improves the prognostic significance of Akt activation in non-small-cell lung cancer tumors

Junji Tsurutani, Junya Fukuoka, Hiroko Tsurutani, Joanna H. Shih, Stephen M. Hewitt, William D. Travis, Jin Jen, Phillip A. Dennis

Research output: Contribution to journalArticle

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Abstract

Purpose: 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. Patients and 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). Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)306-314
Number of pages9
JournalJournal of Clinical Oncology
Volume24
Issue number2
DOIs
StatePublished - Jan 10 2006
Externally publishedYes

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Non-Small Cell Lung Carcinoma
Phosphorylation
Neoplasms
Phospho-Specific Antibodies
Tissue Array Analysis
Lung
Protein-Serine-Threonine Kinases
Squamous Cell Carcinoma
Lung Neoplasms
Carcinogenesis
Adenocarcinoma
Multivariate Analysis
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Evaluation of two phosphorylation sites improves the prognostic significance of Akt activation in non-small-cell lung cancer tumors. / Tsurutani, Junji; Fukuoka, Junya; Tsurutani, Hiroko; Shih, Joanna H.; Hewitt, Stephen M.; Travis, William D.; Jen, Jin; Dennis, Phillip A.

In: Journal of Clinical Oncology, Vol. 24, No. 2, 10.01.2006, p. 306-314.

Research output: Contribution to journalArticle

Tsurutani, J, Fukuoka, J, Tsurutani, H, Shih, JH, Hewitt, SM, Travis, WD, Jen, J & Dennis, PA 2006, 'Evaluation of two phosphorylation sites improves the prognostic significance of Akt activation in non-small-cell lung cancer tumors', Journal of Clinical Oncology, vol. 24, no. 2, pp. 306-314. https://doi.org/10.1200/JCO.2005.02.4133
Tsurutani, Junji ; Fukuoka, Junya ; Tsurutani, Hiroko ; Shih, Joanna H. ; Hewitt, Stephen M. ; Travis, William D. ; Jen, Jin ; Dennis, Phillip A. / Evaluation of two phosphorylation sites improves the prognostic significance of Akt activation in non-small-cell lung cancer tumors. In: Journal of Clinical Oncology. 2006 ; Vol. 24, No. 2. pp. 306-314.
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abstract = "Purpose: 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. Patients and 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). Conclusion: 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.",
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AU - Fukuoka, Junya

AU - Tsurutani, Hiroko

AU - Shih, Joanna H.

AU - Hewitt, Stephen M.

AU - Travis, William D.

AU - Jen, Jin

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N2 - Purpose: 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. Patients and 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). Conclusion: 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.

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