Abstract 3356: Temozolomide resistance in human glioblastoma is associated with marked increase in PDK1 and MGMT expression

Abstract

Abstract Temozolomide has become the standard of care in glioblastoma (GBM) treatment, but a significant number of patients despite optimal treatment are met with recurrence. It is important to understand the molecular mechanisms underlying TMZ resistance for the development of better treatment strategies. In the present study, we evaluated the dynamic relationship between MGMT and resistance to TMZ. We generated a TMZ-resistant 5310R cell line by continuous treatment with 100 µM concentrations of TMZ (3 months) to parent 5310 cells. We tested the efficacy of TMZ on 5310R cells by FACS analysis. 5310R cells showed increased expression of MGMT when compared to parental controls. Also, we observed that the 5310R cells showed alterations in cell morphology, enhanced cell adhesion, increased migration and invasion capacities. Moreover, we observed PDK1, MGMT and EGFR expression to be up-regulated in 5310R cells compared to parental controls. Our previous data suggested that inhibition of PDK1 reverses the Warburg effect, and here we demonstrate that the acquired TMZ resistance in glioma may be associated with promotion of the malignant phenotype. Furthermore, we observed a significant correlation between PDK1, MGMT and EGFR expression in human GBM specimens using immunohistochemistry and Western blot analysis. As treatment with TMZ becomes more ubiquitous in GBM treatment, the significance of the resistant 5310R cell line and an understanding of the metabolic and epigenetic changes will become critical in the development of targeted and effective therapies. Citation Format: William Lee, Kiran Kumar Velpula, Andrew J. Tsung. Temozolomide resistance in human glioblastoma is associated with marked increase in PDK1 and MGMT expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3356. doi:10.1158/1538-7445.AM2014-3356