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黑色素瘤Vemurafenib耐受性值和代谢途径选择之间的相互关系

Pratima Nangia-Makker^1,2, Madison Ahrens¹, Neeraja Purandare³

¹Karmanos Cancer Institute, 421 E. Canfield Avenue, Detroit, MI 48201, USA.

|June 25, 2025

概括

黑色素瘤细胞通过改变其新陈代谢来对韦穆拉芬尼产生抵抗力. 药物耐受性水平决定了特定的代谢途径,为黑色素瘤治疗提供了新的点.

科学领域:

在瘤学瘤学.
代谢研究研究代谢研究
药物耐药性药物耐药性药物耐药性

背景情况:

黑色素瘤迅速发展出对vemurafenib的耐药性,这是BRAFV600突变黑色素瘤的关键疗法.
针对抗性黑色素瘤的代谢转变是有希望的,但药物耐受性和代谢可塑性之间的联系尚未被探索.

研究的目的:

调查vemurafenib耐受水平如何影响BRAFV600E突变黑色素瘤的代谢可塑性.
为了识别与不同维穆拉费尼布耐药水平相关的不同代谢特征.

主要方法:

开发具有差异性药物耐受性的同位素BRAFV600E维穆拉芬尼布耐药 (VemR) 黑色素瘤模型.
使用代谢组,米托板-S1,海马和RNA-seq. 的代谢组和转录组数据的综合分析.

主要成果:

两种VemR模型都显示出对MEK抑制剂的交叉耐药性,但对Wnt/β-catenin抑制剂ICG-001.1.的敏感性.
通过ICG-001治疗,通过降低MITF,ABCB5,-ERK1/2和线粒体呼吸,逆转了维穆拉芬尼的敏感性.
β-catenin信号激活了高耐受性细胞中的TCA循环/OXPHOS和低耐受性细胞中的酸通路,两者都被ICG-001.1.抑制.

结论:

Wnt/β-catenin信号传递在耐维村法尼布诱导的代谢可塑性中起着至关重要的作用.
药物耐药性值直接驱动耐药性黑色素瘤的特定代谢途径转移,使得有针对性的治疗选择.

关键词:

这就是BRAF.在RNA-seqqq.没有信号发送.适应性抵抗是一种适应性抵抗.黑色素瘤是一种黑色素瘤.代谢组代谢组的代谢

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