Herceptin is active in a subset of patients over-expressing the epidermal growth factor receptor (EGFR) c-erbB-2 (HER2) but it is not possible to predict which individuals will respond. Several molecular hypotheses have been proposed for how Herceptin causes tumour regression: one is that the antibody binds to HER2 and causes it to be internalised into breast cancers cells, where it is either degraded or locates to a compartment in which it can no longer signal (or signal in the same way).
The present research aims to explore possible molecular and cellular mechanisms involved in resistance of Herceptin. We are also interested in identifying whether inhibiting other pathways (such as signalling via HER3) would increase the number of patients who show a response. We have created a plasmid containing c-erbB-2 fused to Yellow Fluorescent Protein (c-erbB-2-YFP) and an epidermal growth factor receptor fused to Green Fluorescent Protein (EGFR-GFP). The correct sequence was obtained for both of these and we showed that they react with specific antibodies using western blotting. We have established a system in which we can express c-erbB2-YFP with or without coexpression of the EGFR labelled (or not) with GFP and add Herceptin chemically coupled to the red fluorescent compound Alexa Fluor 568 to see if there is an effect in cell trafficking. We have made a monoclonal antibody called SGP1 that recognises the extracellular domain of HER3 receptor  and we would like to see whether addition of a HER3-specific monoclonal antibody to Herceptin will increase its anticancer activity. If so, SGP1 antibody could be humanised and then both coadministrated with Herceptin in clinical trials.