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首页> 外文期刊>Neoplasia: an international journal for oncology research >Mechanistic Support for Combined MET and AR Blockade in Castration-Resistant Prostate Cancer
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Mechanistic Support for Combined MET and AR Blockade in Castration-Resistant Prostate Cancer

机译：抗阉割前列腺癌组合遇见的机械支持和抗阉割

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A recent phase III trial of the MET kinase inhibitor cabozantinib in men with castration-resistant prostate cancer (CRPC) failed to meet its primary survival end point; however, most men with CRPC have intact androgen receptor (AR) signaling. As previous work supports negative regulation of MET by AR signaling, we hypothesized that intact AR signaling may have limited the efficacy of cabozantinib in some of these patients. To assess the role of AR signaling on MET inhibition, we first performed an in silico analysis of human CRPC tissue samples stratified by AR signaling status (+ or ?), which identified MET expression as markedly increased in AR? samples. In vitro, AR signaling inhibition in AR+ CRPC models increased MET expression and resulted in susceptibility to ligand (HGF) activation. Likewise, MET inhibition was only effective in blocking cancer phenotypes in cells with MET overexpression. Using multiple AR+ CRPC in vitro and in vivo models, we showed that combined cabozantinib and enzalutamide (AR antagonist) treatment was more efficacious than either inhibitor alone. These data provide a compelling rationale to combine AR and MET inhibition in CRPC and may explain the negative results of the phase III cabozantinib study in CRPC. Similarly, the expression of MET in AR? disease, whether due to AR inhibition or loss of AR signaling, suggests potential utility for MET inhibition in select patients with AR therapy resistance and in AR? prostate cancer.
机译：近期III期III阶段对抗阉割前列腺癌（CRPC）的男性的MET激酶抑制剂Cabozantib的试验未能满足其主要存活终点;然而，大多数具有CRPC的男性具有完整的雄激素受体（AR）信号传导。随着以前的工作支持AR信号传导的遇见负调节，我们假设完整的AR信号传导可能限制了Cabozantib在这些患者中的一些疗效。为了评估AR信令对满足抑制的作用，我们首先在由AR信号传导状态（+或α）分层的人CRPC组织样本的硅分析中进行，其鉴定在AR中显着增加的MET表达式表达式样品。在体外，Ar + CRPC模型中的AR信号抑制增加了表达式，导致配体（HGF）活化的敏感性。同样，相似的抑制仅适用于阻断患有过表达的细胞中的癌症表型。在体外和体内模型中使用多个AR + CRPC，我们表明，组合的Cabozantib和烯甲酰胺（AR拮抗剂）处理比单独的抑制剂更有效。这些数据提供了令人讨厌的基本原理来结合AR并在CRPC中满足抑制，并且可以解释CRPC中III期Cabozantib的负面结果。同样，在AR中遇到的表达？疾病，无论是由于AR抑制还是损失AR信号传导，都表明在选择AR治疗抗性和AR中的患者中均衡抑制的潜在效用？前列腺癌。

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