Abstract 316: Identification of SGK1 as a potential therapeutic target in castrate resistance prostate cancer

Abstract

Abstract Introduction: Prostate cancer (PC) is the most common male cancer in the UK, with approximately 1 in 8 men developing the disease within their lifetime (Prostate Cancer UK). The androgen receptor (AR) has a crucial role in the proliferation and progression of prostate cancer. Patients respond to anti-androgen therapy in the early stage of the disease, however many will develop resistance, entering a “castrate-resistant” disease state (CRPC), carrying a very poor prognosis, posing a major clinical challenge (1). The development of second generation anti-androgen therapies, such as Enzalutamide and ARN-509, have shown promise in the treatment of CRPC patients, but response rates of just 50% and the development of resistance to these drugs have limited their success in the clinic (2,3). This study aims to interrogate the global gene expression consequences of anti-androgen resistance in an LNCaP prostate cancer cell line model, resistant to Enzalutamide. In our gene microarray, SGK1 demonstrates high expression in Enzalutamide resistant cells. Our subsequent experiments suggest SGK1 may serve as a biomarker of resistance or perhaps an exploitable target in CRPC. Methods: A gene microarray was used to determine the gene profile of parental LNCaP cells, sensitive to anti-androgen drugs, versus in-house generated LNCaP-Enzalutamide Resistant cells. QPCR to determine the mRNA level of SGK1 +/- Dihydrotestosterone (DHT), +/-Dexamethasone. Western blot used to detect the protein level of the SGK1. IncuCyte used to determine the proliferation. Wound Healing Assay to detect the direction of the cells toward the edges Results: These preliminary data demonstrate an increase in expression of SGK1 in the LNCaP-Enz-R cell line model, compared with parental LNCaP cell, at both the protein and mRNA levels. We have demonstrated that stimulating AR by DHT also increases SGK1 expression at both the protein and mRNA levels, in both cell lines. In addition, it is shown that activation of the glucocorticoid receptor (GR) by stimulation with Dexamethasone increases SGK1 expression at the mRNA level only in LNCaP cells, however high SGK1 expression is observed at the mRNA AND protein level in the LNCaP-Enz-R cell line. Inhibition of SGK1 using small molecular inhibitors significantly decreases proliferation and migration of the LNCaP-Enz-R cell line, whereas no significant difference is seen in the parental, androgen sensitive LNCaP cell line. Conclusion: Increased expression of SGK1 in Enzalutamide, Casodex and ARN509 resistant cell line models was observed, compared with parental LNCaP cells. AR regulates SGK1 in both parental LNCaP and LNCaP-Enz-R cell line models. GR regulates SGK1 in the LNCaP-Enz-R cell line alone. SGK1 has a vital role in the proliferation and migration of the LNCaP-Enz-R cell line model. SGK1 could represent either a future biomarker of Enzalutamide-resistance, or a potential therapeutic target in advanced disease. Citation Format: Massar I. Alsamraae, Urzsula McClurg, Craig N. Robson, Stuart McCracken. Identification of SGK1 as a potential therapeutic target in castrate resistance prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 316. doi:10.1158/1538-7445.AM2017-316