2028 Background: Glioblastoma multiforme is a complex disease that involves the deregulation of overlapping signaling pathways. Constitutive activation of the transcription factor nuclear factor-κB (NF-κB) has been broadly associated with various human cancers, including glioblastomas, and their therapy resistance and may be due to cross-coupling with other oncogenic pathways, such as epidermal growth factor signaling. METHODS: Multidimensional analysis involving gene and transcript data for the endogenous NF-κB modulator IκBα/NFKBIA and clinical patient profiles of 482 glioblastomas/high-grade gliomas from multiple institutions in the United States and The Cancer Genome Atlas Pilot Project. Functional analyses using LN229, U87, and U118 glioblastoma cells, and human embryonic kidney 293T cells with transgene phenotypes for IκBα. IκBα promoter and coding sequence and promoter methylation analyses in a resistance model of 15 glioblastomas cell lines with in vitro and/or in vivo resistance to O6-alkylating agents. RESULTS: We have identified a regulatory circuit between NF-κB and EGFR signaling in glioblastomas, where IκBα binds to EGFR and attenuates EGFR signaling by immobilizing its kinase domain into an inactive conformation. We found the NFKBIA gene at 14q13.2 deleted in 25% of glioblastomas and its occurrence mutually exclusive with EGFR amplification. Loss of NFKBIA associates independently with patient survival. Functional analyses uncover a bona fide tumor suppressor role for IκBα in glioblastoma cells, where it functions to constrain tumorigenic and migratory potential, and induce spontaneous cellular senescence, and apoptosis in response to treatment. IκBα expression is an independent predictor of patient prognosis in multiple glioblastoma populations. Glioblastomas with initially high IκBα expression significantly repress IκBα upon tumor recurrence, suggesting an acquired mechanism to evade its tumor-suppressive and/or chemo-sensitizing effects during tumor progression. CONCLUSIONS: IκBα is a molecular determinant of biological tumor behavior and patient survival in glioblastoma multiforme. Deletion of NFKBIA could present an alternate mechanism to activate EGFR signaling in EGFR non-amplified glioblastomas. No significant financial relationships to disclose.