Molecular mechanisms underlying resistance to androgen deprivation therapy in prostate cancer.
Molecular mechanisms underlying resistance to androgen deprivation therapy in prostate cancer.
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DOI：
10.18632/oncotarget.10901
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发表时间：
2016-09-27
期刊：
影响因子：
--
通讯作者：
Koochekpour S
中科院分区：
文献类型：
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作者：
Wadosky KM;Koochekpour S
前列腺癌(PCA)是西方世界诊断最广泛的男性癌症，虽然低风险和中等风险的前列腺癌患者有多种治疗选择，但转移性患者仅限于雄激素剥夺治疗(ADT)。由于雄激素通过转录因子雄激素受体(AR)及其下游信号通路在促进前列腺上皮细胞生长中的独特作用，这种治疗模式已经存在了75年。在ADT的2到3年内，疾病复发--此时，患者被认为患有去势-复发性前列腺癌(CR-PCA)。PCA对ADT产生抗药性的普遍机制尚未被发现。在这篇综述文章中，我们讨论了PCA逃避ADT的潜在分子机制。一些主要的耐药途径集中在雄激素信号，包括瘤内和肾上腺雄激素的产生，AR的过度表达和扩增，AR突变体的表达，以及结构性活性AR剪接变异体。本文还讨论了ADT耐药的其他机制，包括糖皮质激素受体的激活和DNA修复途径的损伤。新的治疗方法已经被批准用于治疗CR-PCa，但中位生存期只增加了2-8个月。我们讨论了对这些新的ADT药物产生耐药性的可能机制。最后，对转移性或CR-PCa治疗耐药的持续挑战应用“精确肿瘤学”的实用性进行了检验。肯定需要经验验证和临床证据来证明“精确”治疗在提供更有针对性的方法和治疗方法方面的优越性，而不是现有的基于生物“因果”关系的治疗方法。
Prostate cancer (PCa) is the most widely diagnosed male cancer in the Western World and while low- and intermediate-risk PCa patients have a variety of treatment options, metastatic patients are limited to androgen deprivation therapy (ADT). This treatment paradigm has been in place for 75 years due to the unique role of androgens in promoting growth of prostatic epithelial cells via the transcription factor androgen receptor (AR) and downstream signaling pathways. Within 2 to 3 years of ADT, disease recurs—at which time, patients are considered to have castration-recurrent PCa (CR-PCa). A universal mechanism by which PCa becomes resistant to ADT has yet to be discovered. In this review article, we discuss underlying molecular mechanisms by which PCa evades ADT. Several major resistance pathways center on androgen signaling, including intratumoral and adrenal androgen production, AR-overexpression and amplification, expression of AR mutants, and constitutively-active AR splice variants. Other ADT resistance mechanisms, including activation of glucocorticoid receptor and impairment of DNA repair pathways are also discussed. New therapies have been approved for treatment of CR-PCa, but increase median survival by only 2-8 months. We discuss possible mechanisms of resistance to these new ADT agents. Finally, the practicality of the application of “precision oncology” to this continuing challenge of therapy resistance in metastatic or CR-PCa is examined. Empirical validation and clinical-based evidence are definitely needed to prove the superiority of “precision” treatment in providing a more targeted approach and curative therapies over the existing practices that are based on biological “cause-and-effect” relationship.