These findings are important in several folds: first, demonstration of E2F6 as a pivotal downstream target gene of EGFRvIII/ PI3K/AKT/NF‐κB axis; second, established direct connection of E2F6 with EGFRvIII‐promoted GBM progression and TMZ resistance; and finally, provided evidence of E2F6 as a potential therapeutic target and a valuable prognostic marker for GBM, especially the tumors harboring EGFRvIII. Here, NFKB1 is linked to glioblastoma.