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

• Published in: Clinical cancer research Vol. 24; no. 3; pp. 708 - 723
• Main Authors: Wang, Chao, Peng, Guang, Huang, Hai, Liu, Fei, Kong, De-Pei, Dong, Ke-Qin, Dai, Li-He, Zhou, Zhe, Wang, Kai-Jian, Yang, Jun, Cheng, Yan-Qiong, Gao, Xu, Qu, Min, Wang, Hong-Ru, Zhu, Feng, Tian, Qin-Qin, Liu, Dan, Cao, Li, Cui, Xin-Gang, Xu, Chuan-Liang, Xu, Dan-Feng, Sun, Ying-Hao
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01-02-2018
• Subjects: Animals; Antineoplastic Agents - pharmacology; Biomarkers; Cancer; Castration; CD163 antigen; Cell Communication - drug effects; Cell Line, Tumor; Chromatin; Deprivation; Differentiation; Disease Models, Animal; Drug Resistance, Neoplasm; Experimental design; Feedback; Feedback loops; HMGB1 protein; HMGB1 Protein - genetics; HMGB1 Protein - metabolism; Humans; Immunohistochemistry; Immunoprecipitation; Inhibition; Interleukin 6; Interleukin 6 receptors; Macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Male; Metastases; Mice; Monocytes - drug effects; Monocytes - metabolism; Neuroendocrine Cells - drug effects; Neuroendocrine Cells - metabolism; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - pharmacology; Phosphopyruvate hydratase; Positive feedback; Prostate cancer; Prostatic Neoplasms - immunology; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Stat3 protein; STAT3 Transcription Factor - metabolism; Studies; Tissues; Transcription; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; β-Catenin
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-2446

Androgen deprivation therapy (ADT), including enzalutamide, induces resistance in prostate cancer; ADT resistance is associated with neuroendocrine differentiation (NED) and tumor-associated macrophages (TAM). This study aimed to investigate the association between enzalutamide-induced NED and TAMs and its mechanism.
The association between enzalutamide-induced NED and TAMs was investigated by IHC using prostate cancer tissues, enzalutamide-resistant mouse xenografts, and a coculture system. The underlying mechanisms were assessed using
cytokine antibody arrays, ELISAs, chromatin immunoprecipitation, and other methods. An orthotopic prostate cancer mouse model was established to evaluate the
effects of combined IL6 receptor (IL6R) and high mobility group box 1 (HMGB1) inhibition on enzalutamide resistance.
High CD163 expression was observed in ADT-treated prostate cancer or castration-resistant prostate cancer (CRPC) tissues with high levels of neuron-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 β-catenin stabilization. HMGB1-activated TAMs secreted IL6 to augment enzalutamide-induced NED and directly promote HMGB1 transcription via STAT3. Finally, inhibition of the IL6/STAT3 pathway by tocilizumab combined with HMGB1 knockdown inhibited enzalutamide-induced resistance in an orthotopic prostate cancer mouse model.
Enzalutamide elevates HMGB1 levels, which recruits and activates TAMs. Moreover, IL6 secreted by HMGB1-activated TAMs facilitates the enzalutamide-induced NED of prostate cancer, forming a positive feedback loop between NED in prostate cancer and TAMs. The combined inhibition of IL6R and HMGB1 may serve as a new treatment for enzalutamide resistance in patients with advanced or metastatic prostate cancer.
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