Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in Australia, and it is the sixth leading cancer worldwide. The five-year overall survival rate of HNSCC patients is about 40 – 50%. Epidermal growth factor receptor (EGFR) has been shown to play a crucial role in the pathogenesis of HNSCC. EGFR is overexpressed in more than 90% of HNSCC and its expression level correlates with poor prognosis. Upon activation, EGFR is capable of initiating cascades of crucial signalling pathways, such as phosphatidylinositol 3-kinase (PI3K)/Akt pathway and mitogen-activated protein kinases (MAPK) pathway. These pathways are essential in the maintenance of cellular proliferation and survival. Previous studies by Simpson Laboratory show that the inhibition of endocytosis by targeting dynamin is able to enhance antibody-dependent cellular cytotoxicity (ADCC) in response to the anti-EGFR monoclonal antibody, cetuximab. As different trafficking statuses of EGFRs have been shown to alter signalling outcomes, we examined the signalling changes in squamous cell carcinoma (SCC) cells when treated with a combination of dynamin inhibitor and cetuximab. In this study, we found that the combination of drugs now being used in Phase Ib/ II trials is able to inhibit proliferative signalling in both cetuximab-sensitive and cetuximab-resistant SCC cells. Thus the combination therapy shows two separate mechanisms of resistance reversal. From clinical trial, this is the first time dynamin inhibition has been shown to be safe in man.