黑色素瘤vemuurafenib耐受性值与代谢途径选择和Wnt信号参与之间的关系
bioRxiv : the preprint server for biology
|March 17, 2025
概括
在BRAFV600突变黑色素瘤中对维穆拉费尼布的耐药性与Wnt/β-catenin信号传递和代谢途径转移有关. 针对这种途径可以恢复灵敏度并克服适应性抵抗机制.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 代谢学 代谢学 代谢学
背景情况:
- 韦穆拉菲尼布是BRAFV600突变黑色素瘤的关键疗法,但获得的耐药性限制了它的有效性.
- 了解耐药机制对于改善黑色素瘤治疗结果至关重要.
研究的目的:
- 调查与适应性维穆拉费尼布耐药性 (VemR) 相关的代谢和转录学变化.
- 探索Wnt/β-catenin信号传递在VemR中的作用及其与代谢通路利用率和药物耐受性值的关系.
主要方法:
- 在BRAFV600E同源性和患者衍生的黑色素瘤模型中对代谢和转录组数据的综合分析.
- 使用了维村法尼布,MEK,PI3K和Wnt/β-catenin抑制剂 (ICG-001).
- 进行了向代谢物分析,MitoPlate-S1和Mito-stress测定.
主要成果:
- 在VemR细胞中,Wnt/β-catenin信号被上调,导致代谢途径的转变.
- 黑色素瘤细胞具有高耐药性vemurafenib利用Wnt/β-catenin进行线粒体代谢,而耐药性较低的细胞则将其用于酸途径.
- 抑制Wnt/β-catenin信号传递恢复了维穆拉非尼的敏感性和降低了耐药性标志物.
结论:
- 在VemR黑色素瘤中,代谢途径的选择是由药物耐受性值决定的,并由Wnt/β-catenin信号控制.
- 准Wnt/β-catenin信号传递是克服黑色素瘤中维穆拉费尼布耐药性的潜在策略.
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