针对代谢脆弱性:REV-ERB激动剂SR9009增强了索拉费尼布在肝癌中的疗效
Silvia Sabbioni1,2, Paola Guerriero3, Ram C Shankaraiah3,4
1Department of Life Sciences and Biotechnology, University of Ferrara, 44121, Ferrara, Italy. silvia.sabbioni@unife.it.
Cell death discovery
|January 19, 2026
概括
将SR9009与sorafenib结合起来,显示出治疗肝癌的前景. 这种组合有效地通过破坏细胞代谢来向抗索拉芬尼布的肝细胞癌 (HCC).
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症新陈代谢 癌症新陈代谢
背景情况:
- 肝细胞癌 (HCC) 是癌症死亡的主要原因,晚期预后不佳.
- 索拉费尼布是HCC的有价值的治疗方法,但可以产生耐药性.
- 线粒体氧化酸化 (OxPhos) 和Hmox1上调与索拉芬尼布耐药性有关.
研究的目的:
- 为了调查SR9009,REV-ERBα/β激动剂和线粒体呼吸抑制剂,是否可以提高索拉芬尼在肝癌中的疗效.
- 探索组合疗法对HCC细胞影响背后的机制.
主要方法:
- 全基因组RNA-seq分析以确定抵抗机制.
- 使用小鼠和人类肝癌细胞系的体外研究.
- 在体内研究使用异种移植和N-Nitrosodiethylamine (DEN) 诱导的HCC小鼠模型.
主要成果:
- 与SR9009和索拉芬尼的同时治疗在肝癌细胞中显示出协同作用的细胞毒性.
- 这种组合导致自由血红素的增加和线粒体OxPhos的完全抑制.
- 在体内研究表明,在DEN诱导的HCC模型中,在抗索拉芬尼布的瘤中有效,并显著减少瘤.
- 组合疗法耐受良好,没有急性毒性.
结论:
- 针对代谢适应,例如涉及线粒体呼吸的适应,可以提高抗癌疗法的疗效.
- 将索拉费尼布与SR9009结合使用,为晚期HCC提供了一个有前途的治疗策略,特别是在索拉费尼布耐药的情况下.
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