The efficacy of cetuximab in treating cancers is 10-20% due to de novo and acquired resistance. One of the notable mechanisms of action of cetuximab is inhibition of signaling, which is mainly tumourstatic. The tumourlytic mechanistic pathway is the induction of antibody dependent cell mediated cytotoxicity (ADCC). We hypothesize that if antigenic epitopes are arrested on the tumour cell surface by inhibiting their internalisation, increased tumour killing can occur. Our laboratory in vitro experiments showed significant SCC cell killing with cetuximab using dynamin inhibitors to stop ligand-receptor complex endocytosis. This increased killing, reversed innate resistance in resistant cells and increased killing of sensitive cells. We therefore tested our proposition in vivo using NSG mice. Since the NSG mice lack NK cells and other lymphocytes, we humanised their immune system after SCC tumour transplant. Thereafter, we introduced cetuximab/dynamin inhibitor combination therapy. The outcome showed greater statistically significant tumour cell killing in the treated than the control mice in both sensitive and resistant SCC tumours. We subsequently demonstrated that the target receptors of mAb therapy can be redistributed to the tumour surface and reverse tumour heterogeneity for therapeutic target in a Phase I proof-of-mechanism clinical trial. We are now progressing to Phase II combination therapy trials. The great prospect in this mechanistic highway is that it overrides most activating and other mutations that cause de novo or acquired resistance.