Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade.
Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade.
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DOI：
10.1016/j.cell.2013.11.012
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发表时间：
2013-12-05
期刊：
影响因子：
64.5
通讯作者：
Sawyers CL
中科院分区：
文献类型：
--
作者：
Arora VK;Schenkein E;Murali R;Subudhi SK;Wongvipat J;Balbas MD;Shah N;Cai L;Efstathiou E;Logothetis C;Zheng D;Sawyers CL
新型抗雄激素疗法（如恩杂鲁胺）改变了晚期前列腺癌的治疗方式。在此，我们在一个可靠的临床前模型中发现糖皮质激素受体（GR）表达的诱导是耐药肿瘤的一个共同特征，这一发现也在患者样本中得到证实。GR替代雄激素受体（AR）激活一组相似但可区分的靶基因，并且对于维持耐药表型是必需的。GR激动剂地塞米松足以导致对恩杂鲁胺耐药，而GR拮抗剂可恢复敏感性。由于AR介导的对GR表达的反馈抑制的解除，急性AR抑制导致一部分前列腺癌细胞中GR上调。这些发现确立了一种新的机制，即通过在药物暴露时扩增能够通过替代核受体驱动AR靶基因的细胞来逃避AR阻断。
The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Here we identify induction of glucocorticoid receptor (GR) expression as a common feature of drug resistant tumors in a credentialed preclinical model, a finding also confirmed in patient samples. GR substituted for the androgen receptor (AR) to activate a similar but distinguishable set of target genes and was necessary for maintenance of the resistant phenotype. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance whereas a GR antagonist restored sensitivity. Acute AR inhibition resulted in GR upregulation in a subset of prostate cancer cells due to relief of AR-mediated feedback repression of GR expression. These findings establish a novel mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure.
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影响因子：
7.7
作者：
Balbas MD;Evans MJ;Hosfield DJ;Wongvipat J;Arora VK;Watson PA;Chen Y;Greene GL;Shen Y;Sawyers CL
通讯作者：
Sawyers CL
影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
28.2
作者：
Korpal, Manav;Korn, Joshua M.;Zhu, Ping
通讯作者：
Zhu, Ping
影响因子：
45.3
作者：
Efstathiou, Eleni;Titus, Mark;Logothetis, Christopher J.
通讯作者：
Logothetis, Christopher J.
影响因子：
5.3
作者：
Klokk, Tove I.;Kurys, Piotr;Saatcioglu, Fahri
通讯作者：
Saatcioglu, Fahri