The prognostic potential of the epidermal growth factor receptor and nuclear factor kappa B pathways and associated therapeutic strategies in patients with squamous cell carcinoma of the head and neck

摘要: THE PROGNOSTIC POTENTIAL OF EPIDERMAL GROWTH FACTOR RECEPTOR AND NUCLEAR KAPPA B PATHWAYS ASSOCIATED THERAPEUTIC STRATEGIES IN PATIENTS WITH SQUAMOUS CELL CARCINOMA HEAD NECK By Pamela Susan Wirth, Ph.D. A Dissertation submitted in partial fulfillment of the requirements for degree Doctor Philosophy at Virginia Commonwealth University. University, 2010 Major Director: Teresa S. Nadder, Chairman and Associate Professor, Department Clinical Laboratory Sciences Little is known about signaling pathways that contribute to treatment response advanced stage head neck tumors. Increased expression epidermal growth factor receptor (EGFR) downstream such as nuclear kappa (NFκB) are implicated aggressive tumor phenotypes limited therapy. This study explored rationale combining proteasome inhibitor bortezomib with EGFR gefitinib a subset squamous cell carcinomas high gene amplification. Drug responses single agents combination within carcinoma lines were analyzed using MTS assays. The effects on activation itsthree major pathways, Akt, STAT3 MAPK determined by western blotting. status NFκB canonical pathway assessed DNA binding Resistance lower doses was associated elevated activated Akt expression. Gefitinib able effectively inhibit STAT3, HNSCC varying degrees depending status. Bortezomib inhibited TNFα – induced NFκB/RelA but demonstrated variability levels baseline between sensitive resistant lines. suppresses demonstrates additional modes cellular toxicity beyond Further understanding targeted inhibitors may provide novel approaches managing HNSCCs.