Deregulated kinase action in prostate cancer: molecular basis and therapeutic implications.

Abstract

Prostate cancer (CaP) remains the second leading cause of cancer-related mortality in American men. Systemic treatments for metastatic CaP, which causes the majority of deaths, include androgen deprivation therapy and chemotherapy. These treatments induce remissions but do not cure CaP. Novel and functionally diverse therapeutic targets that control the cell biology that drives aggressive CaP progression are needed to overcome treatment resistance. Because signal transduction that mediates CaP cell behavior is tightly regulated by phosphorylation, kinases have attracted interest as alternative targets for CaP treatments. Here, we examine emerging evidence from recent NextGen sequencing and (phospho) proteomics analyses on clinical CaP specimens that were obtained during lethal disease progression to determine the role of deregulated kinase action in CaP growth, treatment resistance, and recurrence. We provide an overview of kinases that are impacted by gene amplification, gene deletion or somatic mutations during the progression from localized treatment-naïve CaP to metastatic castration-resistant CaP or neuroendocrine CaP, and the potential impact of such alterations on aggressive CaP behavior and treatment efficacy. Furthermore, we review knowledge on alterations in the phosphoproteome that occur during the progression to treatment-resistant CaP, the molecular mechanisms in the control of these changes, and the signal transduction associated with them. Finally, we discuss kinase inhibitors under evaluation in CaP clinical trials and the potential, challenges, and limitations to moving knowledge on the CaP kinome forward to new therapeutic strategies.