Disrupting Akt-Wnt/β-catenin signaling suppresses glioblastoma stem cell growth and tumor progression in immunocompetent mice

Glioblastoma (GBM) is an aggressive primary malignant brain tumor in adults with limited therapeutic options and a median survival of 12-18 months post-diagnosis. The PI3K/Akt and Wnt/β-catenin signaling pathways promote GBM cell growth and survival, invasiveness and therapeutic resistance. We hypothesize that inhibiting Akt and β-catenin, which are key central regulatory components of the PI3K/Akt and Wnt/β-catenin pathway, will suppress GBM growth and progression. Mouse glioma cells (CT-2A) and human patient-derived glioma stem cells (N08-30) were treated with MK-2206 or iCRT3 to evaluate effects on cell viability, apoptosis, β-catenin transcriptional activity, and Wnt gene and protein expression in vitro. In vivo, luciferase-expressing CT-2A cells were intracranially implanted in C57BL/6J mice to assess the impact of MK-2206 treatment on tumor progression using bioluminescence imaging. Both MK-2206 and iCRT3 reduced cell viability in a dose-dependent manner, with MK-2206 demonstrating greater potency in reducing viability, inducing apoptosis, and inhibiting Wnt signaling. MK-2206 significantly suppressed tumor growth in vivo and reduced expression of phosphorylated Akt and GSK-3β in tumor tissues, confirming disruption of the Akt and Wnt/β-catenin signaling axis. In summary, MK-2206 outperformed iCRT3 efficacy in vitro, and suppressed GBM progression in vivo. These findings suggest that Akt inhibition via MK-2206 may offer a promising therapeutic strategy for treating GBM characterized by dysregulation of PI3K/Akt or Wnt/β-catenin pathways.