Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis.
Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis.
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DOI：
10.1038/onc.2013.235
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发表时间：
2014-05-29
期刊：
影响因子：
8
通讯作者：
Balk SP
中科院分区：
文献类型：
--
作者：
Yuan X;Cai C;Chen S;Chen S;Yu Z;Balk SP
雄激素受体（雄激素受体，AR）在正常前列腺中的代谢功能在前列腺癌（prostate cancer, PCa）中被绕过来驱动肿瘤生长，并且在前列腺癌的发生发展过程中，雄激素受体还可以通过遗传和表观遗传机制获得新的促生长功能。雄激素剥夺疗法（ADT，手术或药物阉割）是转移性前列腺癌的标准治疗方法，但尽管阉割雄激素水平（阉割抵抗性前列腺癌，CRPC），患者总是复发。许多研究小组的早期研究表明，AR在CRPC中高度表达和转录活跃，并表明来自肾上腺的类固醇有助于这种AR活性。最近的研究表明，CRPC细胞增加了介导肾上腺类固醇合成雄激素的酶的表达，并且可以从胆固醇中合成雄激素。III期临床试验显示，阿比特龙（雄激素合成所需的CYP17A1酶抑制剂，可显著降低雄激素和前体类固醇）和恩杂鲁胺（新型AR拮抗剂）治疗CRPC具有生存优势，现已证实残留雄激素驱动的AR活性对CRPC有重要作用，并导致最近食品和药物管理局批准了这两种药物。不幸的是，接受这些药物治疗的晚期CRPC患者通常在一年内复发，并且AR在复发的肿瘤中似乎是活跃的，但介导这些AR靶向治疗的内在或获得性耐药的分子机制仍有待确定。本文概述了AR在前列腺癌发生和发展中的作用，肿瘤内雄激素合成和AR结构改变在CRPC中驱动AR活性的作用，阿比特龙和恩杂鲁胺的作用机制，以及对这些药物的可能耐药性机制。
The metabolic functions of androgen receptor (AR) in normal prostate are circumvented in prostate cancer (PCa) to drive tumor growth, and the AR also can acquire new growth-promoting functions during PCa development and progression through genetic and epigenetic mechanisms. Androgen deprivation therapy (ADT, surgical or medical castration) is the standard treatment for metastatic PCa, but patients invariably relapse despite castrate androgen levels (castration-resistant PCa, CRPC). Early studies from many groups had shown that AR was highly expressed and transcriptionally active in CRPC, and indicated that steroids from the adrenal glands were contributing to this AR activity. More recent studies showed that CRPC cells had increased expression of enzymes mediating androgen synthesis from adrenal steroids, and could synthesize androgens de novo from cholesterol. Phase III clinical trials showing a survival advantage in CRPC for treatment with abiraterone (inhibitor of the enzyme CYP17A1 required for androgen synthesis that markedly reduces androgens and precursor steroids) and for enzalutamide (new AR antagonist) have now confirmed that AR activity driven by residual androgens makes a major contribution to CRPC, and led to the recent Food and Drug Administration approval of both agents. Unfortunately, patients treated with these agents for advanced CRPC generally relapse within a year and AR appears to be active in the relapsed tumors, but the molecular mechanisms mediating intrinsic or acquired resistance to these AR-targeted therapies remain to be defined. This review outlines AR functions that contribute to PCa development and progression, the roles of intratumoral androgen synthesis and AR structural alterations in driving AR activity in CRPC, mechanisms of action for abiraterone and enzalutamide, and possible mechanisms of resistance to these agents.