Monoclonal antibodies (mAb) are emerging as an important component of cancer therapy, for example, Cetuximab for squamous cell carcinoma (SCC) and Trastuzumab for breast cancer treatment. These antibodies target receptors expressed on the cell plasma membrane but outcomes are unpredictable and the biological determinants of antibody therapy sensitivity remain unknown. We hypothesised that the trafficking status of the epidermal growth factor receptor (EGFR) may impact on the efficacy of the mAb treatments directed at this receptor. Our current work is analyzing whether these pathways also influence the Human Epidermal Growth Factor Receptor 2 (HER2) activity and Trastuzumab efficacy in breast cancer. Analysis of pre-treatment patient SCC tumours indeed showed EGFR trafficking defects which correlated to positive patient outcome after anti-EGFR mAb therapy. By modulating EGFR trafficking in vitro using endocytosis inhibitors which blocked the EGFR on the plasma membrane we were able to enhance anti-EGFR mAb (Cetuximab)-induced SCC tumour cell death by antibody dependent cellular cytotoxicity (ADCC) in both Cetuximab-sensitive and insensitive SCC cells. Using different classes of endocytosis inhibitors we find that this ADCC increase only occurs when the surface EGFR is clustered and this presents a new model for targeted therapy. These studies are now being extended to analyse Trastuzumab action in breast cancer cells. We aim to increase our molecular understanding of HER2 trafficking and the internalisation of Trastuzumab in different breast cancer sub-types. Our initial results suggest that by modifying receptor trafficking we can similarly enhance anti-HER2 mAb (Trastuzumab)-induced cell death by ADCC in both Trastuzumab-sensitive and insensitive breast cancer cell lines. Furthermore, HER2-negative and triple negative breast cancer cell lines could be made responsive to Trastuzumab- and/or Cetuximab-induced ADCC by modulation of receptor trafficking. Findings from this work have potential to impact the clinical management of tumours in which target receptors are spatially regulated.