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Simultaneously targeting cell autonomous and non-cell autonomous oncogenic signaling in glioblastoma

Sourav Ghosh, Yale University School of Medicine & Yale Cancer Center

Grade IV glioblastoma is characterized by increased kinase activity of epidermal growth factor receptor (EGFR); however, EGFR kinase inhibitors have failed to improve survival in individuals with this cancer. We showed that tumor necrosis factor–alpha (TNFalpha) produced in the glioblastoma microenvironment activated atypical protein kinase C (aPKC), thereby producing resistance to EGFR kinase inhibitors. Additionally, we identified that aPKC was required both for paracrine TNFalpha-dependent activation of the transcription factor nuclear factor kappa B (NF-kB) and for tumor cell–intrinsic receptor tyrosine kinase signaling. Targeting aPKC decreased tumor growth in mouse models of glioblastoma, including models of EGFR kinase inhibitor–resistant glioblastoma. Furthermore, aPKC abundance and activity were increased in human glioblastoma tumor cells, and high aPKC abundance correlated with poor prognosis. Thus, targeting aPKC might provide an improved molecular approach for glioblastoma therapy.

Format: Oral communication

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