Boudadi Karim, Antonarakis Emmanuel S
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Baltimore, MD, USA.
Clin Med Insights Oncol. 2016 Mar 16;10(Suppl 1):1-9. doi: 10.4137/CMO.S34534. eCollection 2016.
Despite the introduction of novel therapies that maximally decrease androgen-receptor (AR) signaling activity, metastatic castration-resistant prostate cancer (mCRPC) remains a lethal disease. Even though abiraterone and enzalutamide represent breakthroughs in the treatment of mCRPC and have demonstrated significant survival benefits, a significant proportion of patients have primary resistance to these agents and virtually all patients develop secondary resistance. While the mechanisms of resistance to these agents are not fully understood, many hypotheses of AR-dependent and AR-independent mechanisms are emerging, including upregulation of AR and cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17), induction of AR splice variants, AR point mutations, upregulation of glucocorticoid receptor, activation of alternative oncogenic signaling pathways, neuroendocrine transformation, and immune evasion via programmed death-ligand 1 upregulation. The aim of this review is to summarize the most clinically relevant mechanisms of resistance to novel androgen-directed agents, focusing on escape from enzalutamide and abiraterone.
尽管引入了能最大程度降低雄激素受体（AR）信号传导活性的新型疗法，但转移性去势抵抗性前列腺癌（mCRPC）仍然是一种致命疾病。尽管阿比特龙和恩杂鲁胺代表了mCRPC治疗的突破，并已显示出显著的生存益处，但仍有很大一部分患者对这些药物产生原发性耐药，而且几乎所有患者都会产生继发性耐药。虽然对这些药物的耐药机制尚未完全了解，但许多关于AR依赖性和AR非依赖性机制的假说正在出现，包括AR和细胞色素P450 17α-羟化酶/17,20-裂解酶（CYP17）的上调、AR剪接变体的诱导、AR点突变、糖皮质激素受体的上调、替代致癌信号通路的激活、神经内分泌转化以及通过程序性死亡配体1上调进行的免疫逃逸。本综述的目的是总结对新型雄激素导向药物最具临床相关性的耐药机制，重点关注对恩杂鲁胺和阿比特龙的逃逸。
