Targeting the AKT Pathway in Glioblastoma Multiforme

Abstract

In this study, the therapeutic efficacy of AKT allosteric and ATP competitive inhibitors was investigated in EGFR-amplified SKMG-3 and EGFR-low U-87 cell lines. The IC50 values of AKT inhibitors were determined by cellular viability assay indicating that SKMG-3 cell line was more susceptible to AKT inhibition. These results were further validated by clonogenic assay. In clonogenic assay, both drugs completely inhibited colony forming ability of SKMG-3 cells at 7 μM dose while the effects were relatively less pronounced in U-87 cell line. Western blotting analyses demonstrated that both drugs inhibited AKT activity in both GBM subtypes as determined by dephosphorylation of PRAS40, a downstream target of AKT. Furthermore, both drugs induced rapid apoptosis in SKMG-3 cell line but failed to induce apoptosis in U-87 cell line upon AKT inhibition. In essence, EGFR-amplified SKMG-3 cells are more sensitive to AKT inhibitors than EGFR-low U-87 GBM subtype.