The role of the epidermal growth factor receptor family in prostate cancer and their potential as therapeutic targets

Abstract

The Epidermal Growth Factor Receptor family has been associated with the development of advanced prostate cancer (Carrion-Salip et al., 2012). The family consists of 4 tyrosine kinase receptors – EGFR, HER2, HER3 and HER4 (Burgess, 2008). Previous research has focussed on targeting the EGFR and HER2 receptors however, the role of HER3 in driving PI3K/Akt signalling and mediating drug resistance has shifted the attention towards this signalling partner. This project provides additional understanding regarding the functioning of this receptor family in prostate cancer and establishes the therapeutic potential of a novel pan-inhibitor. The expression levels of HER2 and HER3 were validated in patient biopsy samples and elevated cytoplasmic and nuclear expression was observed with disease progression. Patients differentially expressing low HER2 and strong HER3 levels correlated significantly with poor survival rates. The nuclear translocation of these receptors was further validated in-vitro upon ligand induced activation and their total and phosphorylated forms were found to be present in the nucleus and bound to chromatin. The differential expression of the receptors was also explored in-vitro and in-vivo by transient and stable over-expression and the importance of HER3 mediated signalling was established by the observation of increased MAP Kinase and PI3 Kinase cell signalling pathway activities. This over-activation translated to vital cellular processes in cancer progression, with significant increases in cell proliferation, migration and invasion. The role of these receptors in acquired drug resistance revealed elevated expression and activity of EGFR and HER3 receptors in Lapatinib resistant cells. AZD8931, an EGFR, HER2 and HER3 inhibitor, radically reduced the functioning of these receptors and their regulated cellular processes. The findings of this project opens new avenues for research and suggests the use of a pan-inhibitor as a novel and attractive therapeutic approach in the treatment of advanced prostate cancer.