Glycogen Synthase Kinase 3 Beta Predicts Survival in Resected Adenocarcinoma of the Pancreas

Edgar Ben-Josef, Asha George, William F. Regine, Ross Abrams, Meredith Morgan, Dafydd Thomas, Paul L. Schaefer, Thomas A. DiPetrillo, Mitchel Fromm, William Small, Samir Narayan, Kathryn Winter, Kent A. Griffith, Chandan Guha, Terence M. Williams

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Purpose: GSK3β is a protein kinase that can suppress a number of key oncoproteins. We have previously shown in preclinical models of pancreatic ductal adenocarcinoma (PDAC) that inhibition of GSK3β causes stabilization and nuclear translocation of b-catenin, poor differentiation, proliferation, and resistance to radiation. The objective of this study was to determine its utility as a biomarker of clinical outcomes. Experimental Design: Automated Quantitative Immunofluorescence Analysis (AQUA) of GSK3β was performed on a tissue microarray with samples from 163 patients treated on RTOG 9704. On the basis of findings in an exploratory cohort, GSK3β was analyzed as a categorical variable using its upper quartile (<Q3) as a cut point. Overall survival (OS) and disease-free survival (DFS) were estimated with the Kaplan-Meier method, and GSK3β groupings were compared using the log-rank test. Univariable and multivariable Cox proportional hazards models were used to determine associations between GSK3β and OS/DFS. Results: The 3-year OS rates for GSK3β≥Q3 versus GSK3β <Q3 were 16% (95% confidence intervals; CI, 10%-23%) and 30% (95% CI, 17%-44%), respectively, P = 0.0082. The 3-year DFS rates were 9% (95% CI, 5%-15%) and 20% (95% CI, 9%-33%) respectively, P value = 0.0081. On multivariable analysis, GSK3β was a significant predictor of OS. Patients with GSK3β <Q3 had a 46% reduced risk of dying of pancreatic cancer (HR, 0.54; 95% CI, 0.31-0.96, P value = 0.034). The HR for DFS was 0.65 (95% CI, 0.39-1.07; P value = 0.092). Conclusions: GSK3β expression is a strong prognosticator in PDAC, independent of other known factors such as tumor (T) stage, nodal status, surgical margins and CA19-9.

Original languageEnglish (US)
Pages (from-to)5612-5618
Number of pages7
JournalClinical Cancer Research
Volume21
Issue number24
DOIs
StatePublished - Dec 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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