Activation of MAPK Signaling by CXCR7 Leads to Enzalutamide Resistance in Prostate Cancer
Activation of MAPK Signaling by CXCR7 Leads to Enzalutamide Resistance in Prostate Cancer
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DOI：
10.1158/0008-5472.can-18-2812
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发表时间：
2019-05-15
期刊：
影响因子：
11.2
通讯作者：
Yu, Jindan
中科院分区：
文献类型：
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作者：
Li, Shangze;Fong, Ka-wing;Yu, Jindan
去势抵抗性前列腺癌（CRPC）对新一代雄激素受体（AR）拮抗剂Enzalutamide产生耐药性，是一种致死性疾病。多种前列腺癌模型的转录组分析确定CXCR 7，一种非典型趋化因子受体，是Enzalutamide耐药细胞中上调最多的基因之一。AR通过与基因下游110 kb的增强子结合直接抑制CXCR 7，并且在雄激素剥夺后恢复表达。我们证明了CXCR 7是前列腺癌对恩杂鲁胺敏感性的关键调节因子，并且是体外和体内CRPC生长所必需的。升高的CXCR 7通过配体非依赖性但β-arrestin 2依赖性机制激活MAPK/ERK信号传导。患者标本检查显示，从局限性前列腺癌到CRPC，以及Enzalutamide耐药后，CXCR 7和pERK水平显著升高。临床前研究显示MAPK/ERK抑制剂在抑制Enzalutamide耐药前列腺癌中具有显著疗效。总体而言，这些结果表明，CXCR 7可以作为一个生物标志物的耐药疾病的前列腺癌患者和CXCR 7信号的中断可能是一种有效的策略，以克服resistance.Significance：这些研究结果确定CXCR 7介导的MAPK激活作为一种机制的第二代抗雄激素治疗的阻力，突出了MAPK/ERK抑制剂在CRPC的治疗潜力。
Castration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple prostate cancer models identified CXCR7, an atypical chemokine receptor, as one of the most upregulated genes in enzalutamide-resistant cells. AR directly repressed CXCR7 by binding to an enhancer 110 kb downstream of the gene and expression was restored upon androgen deprivation. We demonstrate that CXCR7 is a critical regulator of prostate cancer sensitivity to enzalutamide and is required for CRPC growth in vitro and in vivo. Elevated CXCR7 activated MAPK/ERK signaling through ligand-independent, but beta-arrestin 2-dependent mechanisms. Examination of patient specimens showed that CXCR7 and pERK levels increased significantly from localized prostate cancer to CRPC and further upon enzalutamide resistance. Preclinical studies revealed remarkable efficacies of MAPK/ERK inhibitors in suppressing enzalutamide-resistant prostate cancer. Overall, these results indicate that CXCR7 may serve as a biomarker of resistant disease in patients with prostate cancer and that disruption of CXCR7 signaling may be an effective strategy to overcome resistance.Significance: These findings identify CXCR7-mediated MAPK activation as a mechanism of resistance to second-generation antiandrogen therapy, highlighting the therapeutic potential of MAPK/ERK inhibitors in CRPC.