Identification and characterization of wild type kinases driving prostate cancer metastasis

Despite numerous oncogenic alterations implicated in metastatic prostate cancer, mutations or DNA amplifications of kinases are rare. We previously demonstrated that 1) expression of wild type (wt) Src in combination with the androgen receptor synergizes to produce aggressive prostate adenocarcinoma, 2) tyrosine phosphorylation increases with prostate cancer stage, and 3) the phosphoproteomic profile of metastatic prostate cancer is different from localized disease. However, the question still remains as to whether wt kinases can drive prostate cancer metastasis and should be regarded as therapeutic targets. To identify wt kinases driving prostate cancer metastasis, we performed phospho-tyrosine, threonine and serine peptide enrichment and quantitative mass spectrometry on metastatic prostate cancer tissues obtained at rapid autopsy. Analysis of this phosphoproteomic dataset combined with bioinformatic analyses of genomic datasets identified ~140 kinases differentially expressed or activated in prostate cancer metastases. To determine which of these kinases function to promote prostate cancer metastasis, we developed an in vitro and in vivo metastasis screen. Out of 140 kinases, 20 kinases promote resistance to anoikis in vitro and metastatic colonization in vivo. Positive kinases include Src, Lyn, and EGFR which have been previously reported to be important in prostate cancer metastasis and thus provide strength to the validity of our screen. In addition we identified kinases with uncharacterized roles in prostate cancer metastasis and of particular interest, several of these kinases promote bone metastasis. We expect our findings will improve our understanding of the mechanistic role of kinase activation in prostate cancer and identify promising new therapeutic targets for metastatic disease.