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Yadav SS, Li J, Stockert JA, et al. Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258) and its Therapeutic Implications. Transl Oncol. 2017;10(3):357-366doi: 10.1016/j.tranon.2017.01.011.
Yadav, S. S., Li, J., Stockert, J. A., Herzog, B., O'Connor, J., Garzon-Manco, L., Parsons, R., Tewari, A. K., & Yadav, K. K. (2017). Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258) and its Therapeutic Implications. Translational oncology, 10(3), 357-366. https://doi.org/10.1016/j.tranon.2017.01.011
Yadav, Shalini S, et al. "Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258) and its Therapeutic Implications." Translational oncology vol. 10,3 (2017): 357-366. doi: https://doi.org/10.1016/j.tranon.2017.01.011
Yadav SS, Li J, Stockert JA, Herzog B, O'Connor J, Garzon-Manco L, Parsons R, Tewari AK, Yadav KK. Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258) and its Therapeutic Implications. Transl Oncol. 2017 Jun;10(3):357-366. doi: 10.1016/j.tranon.2017.01.011. Epub 2017 Mar 24. PMID: 28342996; PMCID: PMC5369368.
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Transl Oncol. 2017 Jun;10(3):357-366. doi: 10.1016/j.tranon.2017.01.011. Epub 2017 Mar 24.

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

Translational oncology

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

Affiliations

  1. Department of Urology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574.
  2. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574.
  3. Department of Urology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574. Electronic address: [email protected].

PMID: 28342996 PMCID: PMC5369368 DOI: 10.1016/j.tranon.2017.01.011

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.

Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

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