Engineered repressors are potent inhibitors of androgen receptor activity
Engineered repressors are potent inhibitors of androgen receptor activity
复制标题
DOI：
10.18632/oncotarget.1360
复制
发表时间：
2014-02-01
期刊：
影响因子：
--
通讯作者：
Bevan, Charlotte L.
中科院分区：
文献类型：
--
作者：
Brooke, Greg N.;Powell, Sue M.;Bevan, Charlotte L.
前列腺癌的生长依赖于雄激素受体（AR）通路，因此这种疾病的治疗通常针对该信号传导轴。这种疗法在大多数患者中是成功的，但在中位2年后总是失败，肿瘤进展到去势抵抗期（CRPC）。许多证据表明，AR仍然是CRPC生长的关键，因此仍然是有效的治疗靶点。在这里，我们描述了一种抑制AR活性的新方法，该方法由与AR配体结合结构域结合的相互作用基序组成，该相互作用基序与抑制结构域融合。这些“工程化阻遏物”是AR活性和前列腺癌细胞生长的有效抑制剂，并且在常规疗法被预测失败的情况下（例如AR突变和改变的辅因子水平）重要地抑制AR。
Prostate cancer growth is dependent upon the Androgen Receptor (AR) pathway, hence therapies for this disease often target this signalling axis. Such therapies are successful in the majority of patients but invariably fail after a median of 2 years and tumours progress to a castrate resistant stage (CRPC). Much evidence exists to suggest that the AR remains key to CRPC growth and hence remains a valid therapeutic target. Here we describe a novel method to inhibit AR activity, consisting of an interaction motif, that binds to the AR ligand-binding domain, fused to repression domains. These 'engineered repressors' are potent inhibitors of AR activity and prostate cancer cell growth and importantly inhibit the AR under circumstances in which conventional therapies would be predicted to fail, such as AR mutation and altered cofactor levels.