Blocking the Feedback Loop between Neuroendocrine Differentiation and Macrophages Improves the Therapeutic Effects of Enzalutamide (MDV3100) on Prostate Cancer

Purpose: Androgen-deprivation therapy (ADT), including enzalutamide, induces resistance in prostate cancer (PCa); ADT resistance is associated with neuroendocrine differentiation (NED) and tumor-associated macrophages (TAMs). This study aimed to investigate the association between enzalutamide-induced NED and TAMs and its mechanism. Experimental Design: The association between enzalutamide-induced NED and TAMs was investigated by immunohistochemistry using PCa tissues, enzalutamide-resistant mouse xenografts and a co-culture system. The underlying mechanisms were assessed using in vitro cytokine antibody arrays, ELISAs, ChIP, etc. An orthotopic PCa mouse model was established to evaluate the in vivo effects of combined IL-6 receptor (IL-6R) and high mobility group box 1 (HMGB1) inhibition on enzalutamide-resistance. Results: High CD163 expression was observed in ADT-treated PCa or castration-resistant PCa (CRPC) tissues with high levels of neuro-specific enolase (NSE) and chromogranin A (CHGA) and in enzalutamide-resistant xenografts, indicating the crucial roles of NED and TAMs in enzalutamide resistance. Specifically, enzalutamide-induced HMGB1 expression facilitated TAM recruitment and polarization and drove NED via b-catenin stabilization. HMGB1-activated TAMs secreted IL-6 to augment enzalutamide-induced NED and directly promote HMGB1 transcription via STAT3. Finally, inhibition of IL-6/STAT3 pathway by tocilizumab combined with HMGB1 knockdown inhibited enzalutamide-induced resistance in an orthotopic PCa mouse model. Conclusions: Enzalutamide elevates HMGB1 levels, which recruits and activates TAMs. Moreover, IL-6 secreted by HMGB1-activated TAMs facilitates the enzalutamide-induced NED of PCa, forming a positive feedback loop between NED in PCa and TAMs. The combined inhibition of IL-6R and HMGB1 may serve as a new treatment for enzalutamide-resistance in patients with advanced or metastatic PCa.

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