The loss of growth control in squamous cell carcinoma of the head and neck (SCCHN) is characterized by acquisition of an autocrine regulatory pathway involving the epidermal growth factor receptor (EGFR). In 2006, the FDA approved the EGFR monoclonal antibody cetuximab for the treatment of SCCHN making it the first new drug approved for this cancer in 45 years. However, despite the ubiquitous expression of EGFR in SCCHN tumors, the clinical response rate to cetuximab as single agent therapy is limited. Co-targeting of oncogenic pathways that are activated in the setting of EGFR blockade in conjunction with cetuximab administration may enhance therapeutic benefits. In the previous funding period, this project focused on elucidating interactions between G-protein-coupled receptors (GPCR) and EGFR in SCCHN with the long-term goal of designing a clinical trial combining EGFR and GPCR inhibitors for head and neck cancer patients. We demonstrated the critical role of Src family kinases (SFK) in GPCR-induced EGFR activation. In the absence of a pan-GPCR inhibitor for clinical use, we have elected to refocus this project on co-targeting of SFK and EGFR in this renewal application. New preliminary data also implicates activation of c-Met in the setting of EGFR resistance or blockade. Our working hypothesis is that persistent signaling through alternate kinases in the setting of EGFR blockade contributes to the limited clinical responses to EGFR targeting in SCCHN. The over-riding hypothesis is that there are defined alternative pathways that bypass a cancer cell's need for EGFR signaling, and represent potential targets for combination therapy. The two candidates we have identified are SFK and c-Met. Completion of these studies will elucidate mechanisms of resistance to EGFR targeting strategies thus facilitating the design of therapeutic regimens to enhance clinical response. We will accomplish this goal by determining: 1) the anti-tumor mechanisms of combined inhibition of EGFR and Src family kinases in SCCHN preclinical models of EGFR inhibitor resistance; 2) the role of HGF/c-Met signaling in mediating resistance of SCCHN to EGFR inhibition and/or as an alternative target for SCCHN therapy; and 3) the therapeutic potential of cetuximab plus dasatinib in SCCHN patients.