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

• DOI: 10.1158/1078-0432.c.6526007.v1
• Publication Date: 2023-04-01T06:30:07Z
• Authors: Chao Wang; Guang Peng; Hai Huang; Fei Liu; De-Pei Kong; Ke-Qin Dong; Li-He Dai; Zhe Zhou; Kai-Jian Wang; Jun Yang; Yan-Qiong Cheng; Xu Gao; Min Qu; Hong-Ru Wang; Feng Zhu; Qin-Qin Tian; Dan Liu; Li Cao; Xin-Gang Cui; Chuan-Liang Xu; Dan-Feng Xu; Ying-Hao Sun
• Keywords: Enzalutamide; Neuroendocrine differentiation

<div>Abstract<p><b>Purpose:</b> Androgen deprivation therapy (ADT), including enzalutamide, induces resistance in prostate cancer; ADT is associated with neuroendocrine differentiation (NED) and tumor-associated macrophages (TAM). This study aimed to investigate the association between enzalutamide-induced NED TAMs its mechanism.</p><p><b>Experimental Design:</b> The was investigated by IHC using cancer tissues, enzalutamide-resistant mouse xenografts, a coculture system. underlying mechanisms were assessed <i>in vitro</i> cytokine antibody arrays, ELISAs, chromatin immunoprecipitation, other methods. An orthotopic model established evaluate vivo</i> effects of combined IL6 receptor (IL6R) high mobility group box 1 (HMGB1) inhibition on enzalutamide resistance.</p><p><b>Results:</b> High CD163 expression observed ADT-treated or castration-resistant (CRPC) tissues levels neuron-specific enolase (NSE) chromogranin A (CHGA) indicating crucial roles resistance. Specifically, HMGB1 facilitated TAM recruitment polarization drove via β-catenin stabilization. HMGB1-activated secreted augment directly promote transcription STAT3. Finally, IL6/STAT3 pathway tocilizumab knockdown inhibited an model.</p><p><b>Conclusions:</b> Enzalutamide elevates levels, which recruits activates TAMs. Moreover, facilitates cancer, forming positive feedback loop IL6R may serve as new treatment for patients advanced metastatic cancer. <i>Clin Cancer Res; 24(3); 708–23. ©2017 AACR</i>.</p></div>