Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258) and its Therapeutic Implications

Abstract 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 d...

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Bibliographic Details
Published in:Translational oncology 2017-06, Vol.10 (3), p.357-366
Main 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
Format: Article
Language:English
Subjects:
Oncology
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Summary:Abstract 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.
ISSN:1936-5233
1936-5233
DOI:10.1016/j.tranon.2017.01.011