After an extensive literature search, it could be stated that novel approaches to treat GBM using mono or combinational therapy of polyphenols and anti-EGFR drugs to target multi signaling pathways (EGFR, JAK/STAT, and PI3K/AKT/mTOR) would help overcome the multiple failures of EGFR–TKI drug trials. This evidence concerns the gene AKT1 and glioblastoma.