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Cancer Res DOI:10.1158/0008-5472.CAN-16-0455

Castration Resistance in Prostate Cancer Is Mediated by the Kinase NEK6.

Publication TypeJournal Article
Year of Publication2017
AuthorsChoudhury, AD, Schinzel, AC, Cotter, MB, Lis, RT, Labella, K, Lock, YJie, Izzo, F, Guney, I, Bowden, M, Li, YY, Patel, J, Hartman, E, Carr, SA, Schenone, M, Jaffe, JD, Kantoff, PW, Hammerman, PS, Hahn, WC
JournalCancer Res
Volume77
Issue3
Pages753-765
Date Published2017 Feb 01
ISSN1538-7445
Abstract

In prostate cancer, the development of castration resistance is pivotal in progression to aggressive disease. However, understanding of the pathways involved remains incomplete. In this study, we performed a high-throughput genetic screen to identify kinases that enable tumor formation by androgen-dependent prostate epithelial (LHSR-AR) cells under androgen-deprived conditions. In addition to the identification of known mediators of castration resistance, which served to validate the screen, we identified a mitotic-related serine/threonine kinase, NEK6, as a mediator of androgen-independent tumor growth. NEK6 was overexpressed in a subset of human prostate cancers. Silencing NEK6 in castration-resistant cancer cells was sufficient to restore sensitivity to castration in a mouse xenograft model system. Tumors in which castration resistance was conferred by NEK6 were predominantly squamous in histology with no evidence of AR signaling. Gene expression profiling suggested that NEK6 overexpression stimulated cytoskeletal, differentiation, and immune signaling pathways and maintained gene expression patterns normally decreased by castration. Phosphoproteome profiling revealed the transcription factor FOXJ2 as a novel NEK6 substrate, with FOXJ2 phosphorylation associated with increased expression of newly identified NEK6 transcriptional targets. Overall, our studies establish NEK6 signaling as a central mechanism mediating castration-resistant prostate cancer. Cancer Res; 77(3); 753-65. ©2016 AACR.

DOI10.1158/0008-5472.CAN-16-0455
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/27899381?dopt=Abstract

Alternate JournalCancer Res.
PubMed ID27899381
PubMed Central IDPMC5290202
Grant ListR01 CA130988 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States