MP90-11 INDUCTION OF NEUROENDOCRINE DIFFERENTIATION IN PROSTATE CANCER CELLS BY DOVITINIB (TKI-258) AND ITS ASSOCIATED THERAPEUTIC IMPLICATIONS

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology IV1 Apr 2016MP90-11 INDUCTION OF NEUROENDOCRINE DIFFERENTIATION IN PROSTATE CANCER CELLS BY DOVITINIB (TKI-258) AND ITS ASSOCIATED THERAPEUTIC IMPLICATIONS Shalini S Yadav, Jinyi Li, Bryan Herzog, Jennifer Stockert, James O'Connor, Luis Garzon Manco, Cordelia Elaiho, Kenneth Haines, Ashutosh K Tewari, and Kamlesh K Yadav Shalini S YadavShalini S Yadav More articles by this author , Jinyi LiJinyi Li More articles by this author , Bryan HerzogBryan Herzog More articles by this author , Jennifer StockertJennifer Stockert More articles by this author , James O'ConnorJames O'Connor More articles by this author , Luis Garzon MancoLuis Garzon Manco More articles by this author , Cordelia ElaihoCordelia Elaiho More articles by this author , Kenneth HainesKenneth Haines More articles by this author , Ashutosh K TewariAshutosh K Tewari More articles by this author , and Kamlesh K YadavKamlesh K Yadav More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2555AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostate cancer remains the second-leading cause of cancer-related deaths in American men with an estimated mortality of nearly 28,000 in 2015 alone. The advent of more potent therapeutics in the recent years has resulted in an increase in the number cases of a rare, aggressive and highly treatment-resistant variant of the disease called neuroendocrine prostate cancer (NEPC), presumably as a means of resistance development. Understanding the mechanism of the NE trans-differentiation process has been hampered due to the poor availability of a universal model system, and is crucial towards determining alternative therapy regimens. Here, we show that treatment of PCa cells with Dovitinib (TKI-258/CHIR-258), a pan receptor tyrosine kinase (RTK) inhibitor induces NE differentiation, both in vitro and in vivo, opening up the possibility of studying the signaling pathways driving NE differentiation. METHODS Cell lines (PC3, LNCaP, DU145 and CW22Rv1) were cultured in RPMI1640 supplemented with 10% fetal bovine serum (FBS). Cell viability was measured using the WST assay (Clontech). Fluorescence microscopy and Western blotting for neuroendocrine markers was performed on cells treated with Dovitinib for 3 weeks. Q-PCR was performed on total RNA isolated from Dovitinib treated cells. Nude mice with xenografted tumors were treated with Dovitinib and tumors analyzed through Western blotting and immunohistochemistry. RESULTS Dovitinib treated LNCaP and PC3 cells showed neurite formation, a characteristic of NE differentiation. This was associated with the expression of NE markers such as neuron specific enolase (NSE), synaptophysin and chromogranin, both at the RNA and protein level. We validated the findings in additional AR +ve cell line (CWR22Rv1) and AR -ve cell line (DU145). Xenografted PC3 tumors in nude mice also showed NE differentiation when mice were treated with Dovitinib. The exact mechanistic underpinnings of this NE differentiation are unclear, but seem to be supported through MAPK and PI3K signaling pathways. CONCLUSIONS Our study for the first time demonstrates that Dovitinib can induce neuroendocrine in AR +ve and AR –ve PCa cell lines, both in vitro and in vivo. It provides a robust tool to study the NE differentiation process in vitro and identify vulnerabilities for therapeutic intervention. The NE differentiation might be a potential mechanism of resistance development to Dovitinib therapy, and thus could have critical clinical implications. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1148-e1149 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Shalini S Yadav More articles by this author Jinyi Li More articles by this author Bryan Herzog More articles by this author Jennifer Stockert More articles by this author James O'Connor More articles by this author Luis Garzon Manco More articles by this author Cordelia Elaiho More articles by this author Kenneth Haines More articles by this author Ashutosh K Tewari More articles by this author Kamlesh K Yadav More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...