Prostate cancer remains a major global health issue and a major cause of morbidity and mortality in men worldwide. Activation of androgen receptor and inactivation of the tumour suppressor gene phosphatase and tensin homologue (PTEN) represent two major events in prostate carcinogenesis. Using a range of clinical resources, in vitro and in vivo models, we explored potential complex interactions among receptor tyrosine kinases (such as HER2/3 and EGFR) and tumour suppressor genes, namely, Sprouty2 (SPRY2) and PTEN. The impacts on their downstream effectors (including PI3K and MAPK) to result in fine regulation of the signalling networks were also considered, which may represent important targets for developing treatment in the context of personalized medicine.