The receptor tyrosine kinase (RTK) ErbB2 is overexpressed in ~30% of breast cancer cases and is known to be associated with an aggressive phenotype and poor patient outcome. There are therapeutic agents that specifically target ErbB2, such as the monoclonal antibodies Herceptin and Perjeta, however the acquisition of resistance to these therapies is a major clinical issue. It has been hypothesised that interactions with other RTKs may facilitate acquired resistance to ErbB2 targeting therapies. As this hypothesis has never been systematically investigated, it begs the question; can ErbB2 utilise an array of other receptor systems to mediate its oncogenic effects and avoid therapeutic inhibition?
To address this question we utilised an interaction screening technique called bimolecular fluorescence complementation to investigate the formation of heterodimers between ErbB2 and a library of 51 RTKs. We have detected an interaction between ErbB2 and 36 of the RTKs in our library, the majority of which have not been previously described. Whilst Herceptin had little effect upon the formation of ErbB2 heterodimers, exposure to Perjeta inhibited the formation of some RTK dimers but also enhanced the formation of a separate subset of heterodimers. Using a receptor tyrosine kinase phosphorylation array we also observed increased tyrosine phosphorylation of alternative RTKs upon treatment of an inherently resistant breast cancer cell line with Perjeta.
These findings suggest that resistance to Perjeta may be mediated via crosstalk between ErbB2 and these alternative receptors. Further characterisation of these novel interactions will determine whether they contribute to the acquisition of resistance to ErbB2 targeting agents and their viability as new therapeutic targets.