Niclosamide enhances abiraterone treatment via inhibition of androgen receptor variants in castration resistant prostate cancer

// Chengfei Liu 1 , Cameron Armstrong 1 , Yezi Zhu 1, 2 , Wei Lou 1 , Allen C. Gao 1, 2, 3 1 Department of Urology, University of California Davis, CA, USA 2 Graduate Program in Pharmacology and Toxicology, University of California Davis, CA, USA 3 UC Davis Comprehensive Cancer Center, University of California Davis, CA, USA Correspondence to: Allen C. Gao, e-mail: acgao@ucdavis.edu Keywords: prostate cancer, niclosamide, abiraterone, androgen receptor variant, resistance Received: December 10, 2015     Accepted: March 10, 2016     Published: March 30, 2016 ABSTRACT Considerable evidence from both clinical and experimental studies suggests that androgen receptor variants, particularly androgen receptor variant 7 (AR-V7), are critical in the induction of resistance to enzalutamide and abiraterone. In this study, we investigated the role of AR-V7 in the cross-resistance of enzalutamide and abiraterone and examined if inhibition of AR-V7 can improve abiraterone treatment response. We found that enzalutamide-resistant cells are cross-resistant to abiraterone, and that AR-V7 confers resistance to abiraterone. Knock down of AR-V7 by siRNA in abiraterone resistant CWR22Rv1 and C4-2B MDVR cells restored their sensitivity to abiraterone, indicating that AR-V7 is involved in abiraterone resistance. Abiraterone resistant prostate cancer cells generated by chronic treatment with abiraterone showed enhanced AR-V7 protein expression. Niclosamide, an FDA-approved antihelminthic drug that has been previously identified as a potent inhibitor of AR-V7, re-sensitizes resistant cells to abiraterone treatment in vitro and in vivo . In summary, this preclinical study suggests that overexpression of AR-V7 contributes to resistance to abiraterone, and supports the development of combination of abiraterone with niclosamide as a potential treatment for advanced castration resistant prostate cancer.