Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer.
Biologic and clinical significance of androgen receptor variants in castration resistant prostate cancer.
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DOI：
10.1530/erc-13-0470
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发表时间：
2014-08
影响因子：
3.9
通讯作者：
Dehm SM
中科院分区：
文献类型：
--
作者：
Ware KE;Garcia-Blanco MA;Armstrong AJ;Dehm SM
随着前列腺癌发展到致命的去势抵抗和转移形式，遗传和表观遗传适应、克隆选择和肿瘤微环境的进化有助于在外部压力的选择压力下出现独特的生物学特征。这些压力包括临床或实验室应用的治疗，以及肿瘤在微观和宏观环境下暴露于激素、旁分泌或自分泌刺激。雄激素受体（AR）是参与前列腺癌病因学和肿瘤发生的关键基因，包括疾病的发生、进展、对初始激素治疗的反应以及随后对激素治疗的抵抗。在某些选择环境下，已经观察到AR信号通路的改变，并有助于抵抗靶向AR激素调节的药物，包括标准雄激素剥夺疗法（ADT），抗雄激素如恩杂鲁胺，以及醋酸阿比特龙雄激素合成抑制。一种这样的抗性机制是合成缺乏典型配体结合域的本构活性AR变体。本文综述了AR变异的病因、特征、生物学特性和对AR变异临床特征有贡献的新数据，并提出了全长AR和AR变异生物标志物验证、评估和临床系统靶向的方法。
As prostate cancer progresses to the lethal castration resistant and metastatic form, genetic and epigenetic adaptation, clonal selection, and evolution of the tumor microenvironment contribute to the emergence of unique biologic characteristics under the selective pressure of external stresses. These stresses include the therapies applied in the clinic or laboratory and the exposures of cancers to hormonal, paracrine, or autocrine stimuli in the context of the tumor micro- and macro-environment. The androgen receptor (AR) is a key gene involved in prostate cancer etiology and oncogenesis, including disease development, progression, response to initial hormonal therapies, and subsequent resistance to hormonal therapies. Alterations in the AR signaling pathway have been observed in certain selection contexts and contribute to the resistance to agents that target hormonal regulation of the AR, including standard androgen deprivation therapy (ADT), anti-androgens such as enzalutamide, and androgen synthesis inhibition with abiraterone acetate. One such resistance mechanism is the synthesis of constitutively active AR variants lacking the canonical ligand binding domain. This review focuses on the etiology, characterization, biologic properties, and emerging data contributing to the clinical characteristics of AR variants, and suggests approaches to full-length AR and AR variant biomarker validation, assessment, and systemic targeting in the clinic.