<div>Prostate cancer (PCa) is the second leading cause of cancer related deaths in American men. In this study, I identify two combinational therapeutics to treat PCa – the combination of enzalutamide and simvastatin, and the combination of GSK126 and metformin, both of which strongly suppress PCa cell growth in vitro and in vivo via inhibiting androgen receptor (AR), an important oncogenic driver for the PCa progression. Simvastatin leads to more AR degradation when combined with enzalutamide. For the combination of GSK126 and metformin, the interaction between enhance of zeste homolog2 (EZH2) and AR is interrupted by GSK126, re-sensitizing EZH2 to metformin. Meanwhile, GSK126 inhibits EZH2’s activity. </div><div><br></div><div>Polo-like kinase 1 (PLK1), a cell cycle regulator, is usually overexpressed in non-small-cell lung cancer (NSCLC). Here, we report that PLK1 overexpression promotes the development of Kras^G12D and Trp53^fl/fl (KP)-driven lung adenocarcinoma (LADC). KP mice harboring transgenic PLK1 (KPPI) display heavier tumor burden, poorer tumor differentiation, and lower survival than KP mice. Mechanistically, PLK1 overexpression enhances the activity of MAPK pathway, via upregulating RET expression in a kinase-dependent manner. Supporting our findings, PLK1 knockout in KP mice reduces RET gene expression, inhibits MAPK pathway activity, and strongly delays LADC development. Therefore, these data reveal that PLK1 functions as an oncogene in KP-driven LADC.</div><div> </div><div><br></div>