Selective Actionable and Druggable Protein Kinases Drive the Progression of Neuroendocrine Prostate Cancer.

Abstract

Current clinical anti-androgen therapies in advanced prostate cancer (PCa) are driving an increased incidence of neuroendocrine prostate cancer (NEPC), a histological variant exhibiting reduced androgen receptor levels and expression of neuroendocrine markers. The mechanisms underlying the development of NEPC are poorly understood. A set of available data from a well-validated xenograft model of NEPC was used to analyze the exact role of protein kinase (PK) played in the development of NEPC. Fifty-four actionable and druggable PKs, mainly enriched in PI3K-Akt, mTOR, and MAPK signaling pathways, were screened out from the drastically changed PKs during NEPC transdifferentiation. Further analysis based on the crosstalk of these above signaling pathways finally singled out 10 PKs considered drivers and therapeutic targets in the development and treatment of NEPC. In vitro, the variation trend of PK expression observed during NEPC transdifferentiation could be recapitulated in PCa cell lines with different malignant degree. The predicted kinase targets exhibited different sensibilities in the restriction of PC3 cell growth. Selective actionable and druggable PKs may act as drivers in the progression of NEPC, and most of them can be used as potential therapeutic targets in clinical practice.