Purpose: Lineage plasticity in prostate cancer—most commonly exemplified by loss of androgen receptor (AR) signaling and a switch from a luminal to alternate differentiation program—is now recognized as a treatment resistance mechanism. Lineage plasticity is a spectrum, but neuroendocrine prostate cancer (NEPC) is the most virulent example. Currently, there are limited treatments for NEPC. Moreover, the incidence of treatment-emergent NEPC (t-NEPC) is increasing in the era of novel AR inhibitors. In contradistinction to de novo NEPC, t-NEPC tumors often express the AR, but AR's functional role in t-NEPC is unknown. Furthermore, targetable factors that promote t-NEPC lineage plasticity are also unclear. Experimental Design: Using an integrative systems biology approach, we investigated enzalutamide-resistant t-NEPC cell lines and their parental, enzalutamide-sensitive adenocarcinoma cell lines. The AR is still expressed in these t-NEPC cells, enabling us to determine the role of the AR and other key factors in regulating t-NEPC lineage plasticity. Results: AR inhibition accentuates lineage plasticity in t-NEPC cells—an effect not observed in parental, enzalutamide-sensitive adenocarcinoma cells. Induction of an AR-repressed, lineage plasticity program is dependent on activation of the transcription factor E2F1 in concert with the BET bromodomain chromatin reader BRD4. BET inhibition (BETi) blocks this E2F1/BRD4-regulated program and decreases growth of t-NEPC tumor models and a subset of t-NEPC patient tumors with high activity of this program in a BETi clinical trial. Conclusions: E2F1 and BRD4 are critical for activating an AR-repressed, t-NEPC lineage plasticity program. BETi is a promising approach to block this program.

中文翻译：

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BET 溴结构域抑制阻断 AR 抑制、E2F1 激活的治疗紧急神经内分泌前列腺癌谱系可塑性程序

目的：前列腺癌的谱系可塑性——最常见的例子是雄激素受体 (AR) 信号丢失和从管腔分化程序向交替分化程序的转变——现在被认为是一种治疗耐药机制。谱系可塑性是一个范围，但神经内分泌前列腺癌 (NEPC) 是最致命的例子。目前，NEPC 的治疗方法有限。此外，在新型 AR 抑制剂时代，治疗中出现的 NEPC（t-NEPC）的发生率正在增加。与新发 NEPC 不同，t-NEPC 肿瘤通常表达 AR，但 AR 在 t-NEPC 中的功能作用尚不清楚。此外，促进 t-NEPC 谱系可塑性的靶向因子也不清楚。实验设计：使用综合系统生物学方法，我们研究了恩杂鲁胺抗性 t-NEPC 细胞系及其亲本，恩杂鲁胺敏感的腺癌细胞系。AR 仍然在这些 t-NEPC 细胞中表达，使我们能够确定 AR 和其他关键因素在调节 t-NEPC 谱系可塑性中的作用。结果：AR 抑制增强了 t-NEPC 细胞的谱系可塑性——这种效应在亲代恩杂鲁胺敏感性腺癌细胞中未观察到。AR 抑制的谱系可塑性程序的诱导依赖于转录因子 E2F1 的激活以及 BET 溴域染色质阅读器 BRD4。BET 抑制 (BETi) 阻断了这个 E2F1/BRD4 调节程序，并减少了 t-NEPC 肿瘤模型和 t-NEPC 患者肿瘤子集的生长，在 BETi 临床试验中具有该程序的高活性。结论：E2F1 和 BRD4 对于激活 AR 抑制的 t-NEPC 谱系可塑性程序至关重要。