中介激酶抑制逆转了晚期前列腺癌的割抗性
Jing Li1, Thomas A Hilimire1,2, Yueying Liu3
1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA.
The Journal of clinical investigation
|March 28, 2024
概括
抑制中介酶CDK8和CDK19可以逆转割抵抗性前列腺癌 (CRPC) 的进展. 结合治疗与割诱导了CRPC模型中的瘤回归和治愈.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症治疗方法 癌症治疗方法
背景情况:
- 介质酶CDK8和CDK19调节基因转录,并与癌症有关.
- 这些激酶在抵抗割的前列腺癌 (CRPC),一种晚期前列腺癌的形式上调调节.
- 雄激素信号差异调节CDK8和CDK19,但两者都在CRPC中升高.
研究的目的:
- 研究中介酶CDK8和CDK19在CRPC进展中的作用.
- 在CRPC模型中评估抑制CDK8和CDK19的治疗潜力.
主要方法:
- 在CRPC异种移植中对CDK8和CDK19的遗传和药理抑制.
- 转录组分析以评估基因表达变化.
- 结合治疗与割的评估.
- 在患者衍生异种移植模型和临床样本中进行评估.
主要成果:
- 抑制CDK8/19逆转了抵抗割的表型,并恢复了对雄激素缺乏的敏感性.
- 与割的联合抑制导致瘤回归和体内治愈.
- 中介酶抑制调节了割对基因表达和瘤微环境的影响.
- 观察到MYC通路的下调,CDK8/19抑制抑制了MYC驱动的CRPC模型.
- 在患者衍生的异种移植中证实有效性,以及与CRPC进展和存活相关的Mediator kinase活性基因特征.
结论:
- 调解者激酶CDK8和CDK19驱动CRPC中无原体的生长.
- 向CDK8/19代表了CRPC的一个有前途的治疗策略.
- 结合CDK8/19抑制剂与割的联合治疗显示出治疗晚期前列腺癌的巨大潜力.
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