[1810] aPKC-Dependent EGFR and NF-kB Signaling Co-Operate To Promote Glioblastoma Invasion

Anthony S Perry, Yael Kusne, Maurice Jabbour, Edward Mandell, Wendy McDonough, Kenneth Aldape, Michael E Berens, Joseph C Loftus, Elisabeth J Rushing, Sourav Ghosh. Brigham and Women's Hospital, Boston, MA; Barrow Neurological Institute/St. Joseph's Hospital, Phoenix, AZ; Arizona State University, Tempe, AZ; The University of Arizona, Tucson, AZ; Translational Genomics Research Institute, Phoenix, AZ; MD Anderson Cancer Center, Houston, TX; Mayo Clinic Arizona, Scottsdale, AZ; Armed Forces Institute of Pathology, Washington, DC

Background: Glioblastoma multiforme (GBM) is the most common primary brain tumor with an average untreated survival of three months and 14 months with therapy. Successful anti-EGFR targeted therapy has proven elusive despite profound success in other tumors and clear pathogenesis in GBM. This resistance may be due to shunting of tumor signaling. We present evidence of EGFR kinase inhibitor resistance through activation of NF-κB signaling, mediated by the protein kinase aPKC.
Design: Using a co-culture model of human GBM cells and macrophages, we measured GBM invasion with NF-kB and EGFR signaling modulators. In vivo testing included demonstration of activity in human GBM tissue arrays and patient survival was compared by the cox hazard ratio between aPKC, EGFR groups.
Results: Anti-TNF-a antibody or inhibition of NF-kB signaling within GBM cells attenuates invasion of GBM in an EGFR-independent manner. Upon co-culture of GBM cells with macrophages, autocrine production of TNF-a and NF-kB signaling is increased. This was dependent on protein kinase aPKC association with scaffold proteins regulating the TNF-α dependent transcription of IL-1b, IL-8, TNF-a and MCP-1. The aPKC-Par6 complex also regulated EGF-dependent Rac activation, transcription of a number of EGF-dependent invasion-associated genes (CD44, VCAM, MMP9, uPAR), and the actin cytoskeleton. It was found that aPKC bridges both EGFR and NF-kB pathways in GBM. Silencing of aPKC was more effective in inhibiting GBM invasion, particularly under GBM cell-macrophage co-culture conditions. High activity of aPKC was shown in GBM tissue arrays with a significant correlation between macrophage/microglial infiltration, aPKC and poor GBM survival independent of EGFR expression.
Conclusions: In conclusion, macrophage derived TNF-α activates NF-κB signaling and was found to confer resistance to EGFR kinase inhibitors through aPKC. The protein kinase aPKC is a critical component of both EGFR and NF-kB signaling pathways in GBM cells and may be an attractive therapeutic target for future studies.
Category: Neuropathology

Monday, March 19, 2012 9:30 AM

Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 280, Monday Morning

 

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