Inhibition of the Wnt/β-Catenin Pathway Overcomes Resistance to Enzalutamide in Castration-Resistant Prostate Cancer.
Inhibition of the Wnt/β-Catenin Pathway Overcomes Resistance to Enzalutamide in Castration-Resistant Prostate Cancer.
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DOI：
10.1158/0008-5472.can-17-3006
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发表时间：
2018-06-15
期刊：
影响因子：
11.2
通讯作者：
Liu X
中科院分区：
文献类型：
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作者：
Zhang Z;Cheng L;Li J;Farah E;Atallah NM;Pascuzzi PE;Gupta S;Liu X
Enzalutamide是第二代非甾体类抗雄激素药物，临床批准用于治疗去势抵抗性前列腺癌（CRPC），但对内分泌治疗的耐药性限制了其在这种情况下的成功。虽然雄激素受体（AR）与治疗失败有关，但这种失败的机制尚未阐明。生物信息学分析预测，Wnt/β-catenin通路的激活及其与AR的相互作用在Enzalutamide耐药的获得中起主要作用。为了验证这一发现，我们发现在恩杂鲁胺耐药细胞中β-catenin和AR上调，部分原因是β-TrCP介导的泛素化减少。尽管Enzalutamide敏感细胞中Wnt/β-连环蛋白途径的激活导致耐药性，但β-连环蛋白抑制剂ICG 001与Enzalutamide联合使用在各种模型中协同抑制干细胞样标志物的表达、细胞增殖和肿瘤生长。临床数据集分析揭示了PCa不同阶段的分子模式转变，其中我们检测到AR和β-catenin表达之间的显著相关性。这些数据确定了Wnt/β-连环蛋白通路的激活是导致Enzalutamide耐药的主要机制，并证明了对具有所述耐药高风险的患者进行分层的可能性。
Enzalutamide is a second-generation nonsteroidal antiandrogen clinically approved for the treatment of castration-resistant prostate cancer (CRPC), yet resistance to endocrine therapy has limited its success in this setting. Although the androgen receptor (AR) has been associated with therapy failure, the mechanisms underlying this failure have not been elucidated. Bioinformatics analysis predicted that activation of the Wnt/β-catenin pathway and its interaction with AR play a major role in acquisition of enzalutamide resistance. To validate the finding, we show upregulation of β-catenin and AR in enzalutamide-resistant cells, partially due to reduction of β-TrCP mediated-ubiquitination. While activation of the Wnt/β-catenin pathway in enzalutamide-sensitive cells led to drug resistance, combination of β-catenin inhibitor ICG001 with enzalutamide inhibited expression of stem-like markers, cell proliferation, and tumor growth synergistically in various models. Analysis of clinical datasets revealed a molecule pattern shift in different stages of PCa, where we detected a significant correlation between AR and β-catenin expression. These data identify activation of the Wnt/β-catenin pathway as a major mechanism contributing to enzalutamide resistance and demonstrate the potential to stratify patients with high risk of said resistance.