Crona Daniel J, Whang Young E
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Cancers (Basel). 2017 Jun 12;9(6):67. doi: 10.3390/cancers9060067.
Despite the initial efficacy of androgen deprivation in prostate cancer, virtually all patients progress to castration-resistant prostate cancer (CRPC). Androgen receptor (AR) signaling is critically required for CRPC. A new generation of medications targeting AR, such as abiraterone and enzalutamide, has improved survival of metastatic CRPC (mCRPC) patients. However, a significant proportion of patients presents with primary resistance to these agents, and in the remainder, secondary resistance will invariably develop, which makes mCRPC the lethal form of the disease. Mechanisms underlying progression to mCRPC and treatment resistance are extremely complex. AR-dependent resistance mechanisms include amplification, point mutations, expression of constitutively active splice variants, and altered intratumoral androgen biosynthesis. AR-independent resistance mechanisms include glucocorticoid receptor activation, immune-mediated resistance, and neuroendocrine differentiation. The development of novel agents, such as seviteronel, apalutamide, and EPI-001/EPI-506, as well as the identification and validation of novel predictive biomarkers of resistance, may lead to improved therapeutics for mCRPC patients.
尽管雄激素剥夺疗法对前列腺癌具有初始疗效，但几乎所有患者都会进展为去势抵抗性前列腺癌（CRPC）。CRPC严重依赖雄激素受体（AR）信号传导。新一代靶向AR的药物，如阿比特龙和恩杂鲁胺，已改善了转移性CRPC（mCRPC）患者的生存率。然而，相当一部分患者对这些药物存在原发性耐药，而在其余患者中，继发性耐药也不可避免地会出现，这使得mCRPC成为该疾病的致命形式。mCRPC进展和治疗耐药的潜在机制极其复杂。AR依赖性耐药机制包括扩增、点突变、组成型活性剪接变体的表达以及肿瘤内雄激素生物合成的改变。AR非依赖性耐药机制包括糖皮质激素受体激活、免疫介导的耐药和神经内分泌分化。新型药物如西维特罗奈、阿帕鲁胺和EPI-001/EPI-506的开发，以及新型耐药预测生物标志物的识别和验证，可能会改善mCRPC患者的治疗效果。
