突变的Kras拷贝数定义了代谢重编程和治疗易感性
Emma M Kerr1, Edoardo Gaude1, Frances K Turrell1
1MRC Cancer Unit, University of Cambridge, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
Nature
|February 25, 2016
概括
肺癌中的RAS/MAPK途径放松涉及KRAS突变. 具有KRAS复制增长的瘤表现出不同的代谢特征,这表明Kras突变肺癌的治疗策略不同.
科学领域:
- 癌症学
- 分子生物学
- 癌症新陈代谢
背景情况:
- 在非小细胞肺癌 (NSCLC) 中,RAS/MAPK信号通路经常受到改变,通常是由KRAS突变驱动的.
- 虽然单个突变的克拉斯基因基因可以在小鼠中引发肺瘤,但进展需要进一步的遗传变化,包括克拉斯基因基因基因的复制量增加.
研究的目的:
- 在肺癌中研究不同Kras基因型 (同卵性与异卵性) 之间的表型和代谢差异.
- 确定Kras等位基丰富是否影响瘤代谢和体内治疗的脆弱性.
主要方法:
- 对Kras(G12D/G12D) 和Kras(G12D/+) 小鼠胚胎纤维细胞和肺癌细胞进行比较分析.
- 代谢概况,包括葡萄糖代谢,三酸循环活性和谷氨酸生物合成.
- 使用自发性小鼠肺瘤的体内研究,Kras基因含量各不相同.
主要成果:
- 克拉斯 (G12D/G12D) 细胞表现出一种代谢转向糖解和增强的谷氨合成以进行解毒.
- 这种代谢重新连接在晚期克拉斯同卵性NSCLC和具有克拉斯复制增长的自发小鼠肺瘤中观察到,但在早期瘤中没有.
- 突变的克拉斯复制增加在侵袭性肺瘤中产生特定的代谢依赖性.
结论:
- 突变的KRAS肺瘤是异质的,其代谢特征,预后和治疗易感性是基于基含量.
- 在肺癌进展过程中,Kras等位基丰富会导致显著的代谢变化.
- 针对这些独特的代谢依赖提供了治疗激进突变KRAS肺癌的潜在策略.
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