Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100.
Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100.
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DOI：
10.1158/0008-5472.can-11-3980
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发表时间：
2012-05-01
期刊：
影响因子：
11.2
通讯作者：
Attard G
中科院分区：
文献类型：
--
作者：
Richards J;Lim AC;Hay CW;Taylor AE;Wingate A;Nowakowska K;Pezaro C;Carreira S;Goodall J;Arlt W;McEwan IJ;de Bono JS;Attard G
前列腺癌进展可能与去势和/或抗雄激素治疗后获得的雄激素受体（AR）突变相关。阿比特龙是一种合理设计的CYP 17 A1抑制剂，最近被批准用于治疗紫杉醇治疗的去势抵抗性前列腺癌（CRPC），通常是有效的，但需要与糖皮质激素共同给药以减少副作用。在此，我们假设阿比特龙治疗后的疾病进展可能继发于糖皮质激素诱导的突变AR激活。我们发现，CRPC患者的泼尼松龙血浆水平足够高以激活突变型AR。盐皮质激素受体拮抗剂，如螺内酯和依普利酮，用于治疗与盐皮质激素过量相关的副作用，也与野生型和突变型AR结合并通过野生型和突变型AR激活信号传导。阿比特龙抑制AR阳性前列腺癌细胞的体外增殖和AR调节的基因表达，这可以通过除了抑制类固醇生成之外的AR拮抗作用来解释。有趣的是，依普利酮对突变体AR的激活可被MDV 3100、比卡鲁胺或更高浓度的阿比特龙抑制。因此，阿比特龙暴露量增加至该阈值以上可逆转继发于残留配体或联合给药药物激活AR的耐药性。总之，我们的研究结果为联合CYP 17 A1抑制和AR拮抗作用的临床评价提供了强有力的依据。
Prostate cancer progression can be associated with androgen receptor (AR) mutations acquired following treatment with castration and/or an anti-androgen. Abiraterone, a rationally-designed inhibitor of CYP17A1 recently approved for the treatment of docetaxel-treated castration-resistant prostate cancer (CRPC), is often effective, but requires co-administration with glucocorticoids to curtail side effects. Here we hypothesized that progressive disease on abiraterone may occur secondary to glucocorticoid-induced activation of mutated AR. We found that prednisolone plasma levels in CRPC patients were sufficiently high to activate mutant AR. Mineralocorticoid receptor antagonists, such as spironoloactone and eplerenone that are used to treat side-effects related to mineralocorticoid excess, also bound to and activated signaling through both wild-type and mutant AR. Abiraterone inhibited in vitro proliferation and AR-regulated gene expression of AR-positive prostate cancer cells, which could be explained by AR antagonism in addition to inhibition of steroidogenesis. Interestingly, activation of mutant AR by eplerenone was inhibited by MDV3100, bicalutamide or greater concentrations of abiraterone. Therefore, an increase in abiraterone exposure above this threshold could reverse resistance secondary to activation of AR by residual ligands or co-administered drugs. Together, our findings provide a strong rationale for clinical evaluation of combined CYP17A1 inhibition and AR antagonism.