Prostate cancer (PCa) remains the second-leading cause of cancer-related deaths 
in American men with an estimated mortality of more than 26,000 in 2016 alone. 
Aggressive and metastatic tumors are treated with androgen deprivation therapies 
(ADT); however, the tumors acquire resistance and develop into lethal castration 
resistant prostate cancer (CRPC). With the advent of better therapeutics, the 
incidences of a more aggressive neuroendocrine prostate cancer (NEPC) variant 
continue to emerge. Although de novo occurrences of NEPC are rare, more than 25% 
of the therapy-resistant patients on highly potent new-generation anti-androgen 
therapies end up with NEPC. This, along with previous observations of an 
increase in the number of such NE cells in aggressive tumors, has been suggested 
as a mechanism of resistance development during prostate cancer progression. 
Dovitinib (TKI-258/CHIR-258) is a pan receptor tyrosine kinase (RTK) inhibitor 
that targets VEGFR, FGFR, PDGFR, and KIT. It has shown efficacy in mouse-model 
of PCa bone metastasis, and is presently in clinical trials for several cancers. 
We observed that both androgen receptor (AR) positive and AR-negative PCa cells 
differentiate into a NE phenotype upon treatment with Dovitinib. The NE 
differentiation was also observed when mice harboring PC3-xenografted tumors 
were systemically treated with Dovitinib. The mechanistic underpinnings of this 
differentiation are unclear, but seem to be supported through MAPK-, PI3K-, and 
Wnt-signaling pathways. Further elucidation of the differentiation process will 
enable the identification of alternative salvage or combination therapies to 
overcome the potential resistance development.