Niclosamide and bicalutamide combination treatment overcomes enzalutamide and bicalutamide resistant prostate cancer

摘要

Activation of the androgen receptor (AR) and its splice variants is linked to advanced prostate cancer and drives resistance to antiandrogens. The roles of AR and AR variants in the development of resistance to androgen deprivation therapy (ADT) and bicalutamide treatment, however, are still incompletely understood. To determine whether AR variants play a role in bicalutamide resistance, we developed bicalutamide resistant LNCaP cells (LNCaP-BicR) and found that these resistant cells express significantly increased levels of AR variants, particularly AR-V7, both at the mRNA and protein levels. Exogenous expression of AR-V7 in bicalutamide sensitive LNCaP cells confers resistance to bicalutamide treatment. Knockdown of AR-V7 in bicalutamide and enzalutamide resistant CWR22Rv1, enzalutamide resistant C4-2B (C4-2B MDVR) and LNCaP-BicR cells reversed bicalutamide resistance. Niclosamide, a potent inhibitor of AR variants, significantly enhanced bicalutamide treatment. Niclosamide and bicalutamide combination treatment not only suppressed AR and AR variants expression and inhibited their recruitment to the PSA promoter, but also significantly induced apoptosis in bicalutamide and enzalutamide resistant CWR22Rv1 and C4-2B MDVR cells. In addition, combination of niclosamide with bicalutamide inhibited the growth of enzalutamide resistant tumors. In summary, our results demonstrate that AR variants, particularly AR-V7, drive bicalutamide resistance and that targeting AR-V7 with niclosamide can re-sensitize bicalutamide resistant cells to bicalutamide treatment. Furthermore, combination of niclosamide with bicalutamide inhibits enzalutamide resistant tumor growth, suggesting that the combination of niclosamide and bicalutamide could be a potential cost effective strategy to treat advanced prostate cancer in patients, including those who fail to respond to enzalutamide therapy.