Abstract
Abstract Prostate cancer is the most common type of cancer in men, with approximately 181,000 new cases diagnosed in 2016. Due to the central role of the androgen receptor (AR) in prostate development and more importantly prostate cancer cell survival and proliferation, strategies targeting AR have been the mainstay therapy for over 70 years. However, despite potent inhibition of AR pathway activation, many patients develop castration-resistant prostate cancer (CRPC). Second-line therapies, such as enzalutamide, has increased overall survival in CRPC, but resistance to these therapies inevitably emerges, suggesting that other pathways apart from AR signalling are contributing to the failure of treatments. We have previously demonstrated that SOX2 [SRY (sex determining region Y)-box 2] is an AR-repressed gene that is expressed in a large percentage of high Gleason grade prostate tumours, as well as in most metastases. Additionally, expression of SOX2 within a castration-sensitive cell line is sufficient to enable castration-resistant tumor formation in vivo, and enzalutamide resistance in vitro. In prostate cancer, SOX2 is not found with its normal stem cell co-factors, NANOG and OCT4, leading to the hypothesis that SOX2 is interacting with a novel co-factor in prostate cancer to regulate expression of genes promoting castration-resistance. A chromatin-immunoprecipitation experiment in a castration-resistant prostate cancer cell line was performed to determine if SOX2 binds the same genes and activates similar pathways in prostate cancer as in embryonic stem cells. Approximately half of the SOX2 bound genes in the CRPC cell line were shared with the embryonic stem cell line, and these genes are involved in signalling pathways and maintenance of stem cell pluripotency; the genes bound uniquely in the CRPC cell line are present in pathways involved with metabolic processes. To identify potential binding partners of SOX2, computational analysis of the sites bound by SOX2 in the promoter regions of target genes determined the FOXA1 motif is within close proximity to the SOX2 motif, and the physical interaction of these proteins was confirmed through co-immunoprecipitation. Further understanding of SOX2 target genes and the pathways that SOX2 activates in the presence of enzalutamide will be crucial to identify mechanisms of resistance and enable the development of novel therapies for castration-resistant prostate cancer. Citation Format: Larischa de Wet, Anthony Williams, Marc Gillard, Steve Kregel, Tzintzuni Garcia, Erin McAuley, Ryan Brown, Donald Vander Griend. The role of SOX2 in promoting resistance to AR-targeted therapies in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3348.
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