Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258) and its Therapeutic Implications. Academic Article uri icon


  • 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.

published proceedings

  • Transl Oncol

altmetric score

  • 1

author list (cited authors)

  • Yadav, S. S., Li, J., Stockert, J. A., Herzog, B., O'Connor, J., Garzon-Manco, L., ... Yadav, K. K.

citation count

  • 24

complete list of authors

  • Yadav, Shalini S||Li, Jinyi||Stockert, Jennifer A||Herzog, Bryan||O'Connor, James||Garzon-Manco, Luis||Parsons, Ramon||Tewari, Ashutosh K||Yadav, Kamlesh K

publication date

  • January 2017