Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258) and its Therapeutic Implications.
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.
Department of Urology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574.
Shalini S
SS
Yadav
Department of Urology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574.
Jinyi
J
Li
Department of Urology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574.
Jennifer A
JA
Stockert
Department of Urology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574.
Bryan
B
Herzog
Department of Urology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574.
James
J
O'Connor
Department of Urology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574.
Luis
L
Garzon-Manco
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574.
Ramon
R
Parsons
Department of Urology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574.
Ashutosh K
AK
Tewari
Department of Urology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029-6574. Electronic address: kamlesh.yadav@mountsinai.org.
Kamlesh K
KK
Yadav