Constitutive activity of the androgen receptor.
Constitutive activity of the androgen receptor.
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DOI：
10.1016/b978-0-12-417197-8.00011-0
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Dehm, Scott M
中科院分区：
文献类型：
--
作者：
Chan, Siu Chiu;Dehm, Scott M
前列腺癌（PCa）是美国最常见的癌症。雄激素受体（AR）信号传导轴是前列腺癌病理生理学所有阶段的中心，并作为内分泌治疗的主要靶点。该疾病的最晚期阶段，去势抵抗性前列腺癌（CRPC），目前是不可治愈的，并占大多数PCa死亡率。在这篇综述中，我们强调了AR信号轴可以绕过内分泌靶向治疗并驱动CRPC进展的机制。这些机制包括生长因子、细胞因子和炎症信号传导途径的改变、转录辅助调节因子的表达或活性改变、AR点突变和导致AR蛋白过表达的AR基因扩增。此外，我们将讨论缺乏COOH末端配体结合结构域的组成型活性AR剪接变体（AR-Vs）的合成机制，以及AR-Vs在支持CRPC治疗耐药性中的作用和调节。最后，我们总结了针对离散AR功能域的抑制剂的持续发展以及用于监测患者AR信号传导轴的新生物标志物的状态。
Prostate cancer (PCa) is the most frequently diagnosed cancer in the United States. The androgen receptor (AR) signaling axis is central to all stages of PCa pathophysiology and serves as the main target for endocrine-based therapy. The most advanced stage of the disease, castration resistant prostate cancer (CRPC), is presently incurable and accounts for most PCa mortality. In this review, we highlight the mechanisms by which the AR signaling axis can bypass endocrine-targeted therapies and drive progression of CRPC. These mechanisms include alterations in growth factor, cytokine, and inflammatory signaling pathways, altered expression or activity of transcriptional co-regulators, AR point mutations, and AR gene amplification leading to AR protein overexpression. Additionally, we will discuss the mechanisms underlying the synthesis of constitutively active AR splice variants (AR-Vs) lacking the COOH-terminal ligand binding domain, as well as the role and regulation of AR-Vs in supporting therapeutic resistance in CRPC. Finally, we summarize the ongoing development of inhibitors targeting discrete AR functional domains as well as the status of new biomarkers for monitoring the AR signaling axis in patients.