An F876L Mutation in Androgen Receptor Confers Genetic and Phenotypic Resistance to MDV3100 (Enzalutamide)
An F876L Mutation in Androgen Receptor Confers Genetic and Phenotypic Resistance to MDV3100 (Enzalutamide)
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DOI：
10.1158/2159-8290.cd-13-0142
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发表时间：
2013-09-01
期刊：
影响因子：
28.2
通讯作者：
Zhu, Ping
中科院分区：
文献类型：
--
作者：
Korpal, Manav;Korn, Joshua M.;Zhu, Ping
去势抵抗性前列腺癌（CRPC）是最具侵袭性、无法治愈的前列腺癌。MDV3100 （enzalutamide）是一种雄激素受体（AR）拮抗剂，已被批准用于转移性CRPC男性患者的临床应用。尽管这种化合物显示出临床疗效，但许多最初的应答者后来产生了耐药性。为了揭示相关的耐药机制，我们建立了LNCaP前列腺癌细胞对MDV3100的自发耐药模型。详细的表征显示，AR中F876L突变的出现与AR对MDV3100的反应减弱以及治疗期间持续的增殖相关。功能研究证实，AR F876L具有拮抗剂到激动剂的转换，可驱动表型抗性。最后，用不同的抗雄激素或细胞周期蛋白依赖性激酶（CDK） 4/6抑制剂治疗可有效拮抗AR F876L的功能。总之，这些发现表明F876L的出现可能(i)作为预测药物敏感性的一种新的生物标志物，（ii）预测对MDV3100的“戒断”反应，（iii）与其他抗雄激素或CDK4/6抑制剂适当靶向。意义：我们发现了AR中F876L激动剂开关突变，该突变赋予抗雄激素药物MDV3100的遗传和表型抗性。基于这一发现，我们提出了新的治疗策略来治疗出现这种AR突变的前列腺癌患者。(c) 2013年aacr。
Castration-resistant prostate cancer (CRPC) is the most aggressive, incurable form of prostate cancer. MDV3100 (enzalutamide), an antagonist of the androgen receptor (AR), was approved for clinical use in men with metastatic CRPC. Although this compound showed clinical efficacy, many initial responders later developed resistance. To uncover relevant resistant mechanisms, we developed a model of spontaneous resistance to MDV3100 in LNCaP prostate cancer cells. Detailed characterization revealed that emergence of an F876L mutation in AR correlated with blunted AR response to MDV3100 and sustained proliferation during treatment. Functional studies confirmed that AR F876L confers an antagonist-to-agonist switch that drives phenotypic resistance. Finally, treatment with distinct antiandrogens or cyclin-dependent kinase (CDK) 4/6 inhibitors effectively antagonized AR F876L function. Together, these findings suggest that emergence of F876L may (i) serve as a novel biomarker for prediction of drug sensitivity, (ii) predict a "withdrawal" response to MDV3100, and (iii) be suitably targeted with other antiandrogens or CDK4/6 inhibitors.SIGNIFICANCE: We uncovered an F876L agonist-switch mutation in AR that confers genetic and phenotypic resistance to the antiandrogen drug MDV3100. On the basis of this finding, we propose new therapeutic strategies to treat patients with prostate cancer presenting with this AR mutation. (C) 2013 AACR.