与抗KRAS (G12C) 抑制相关的多种变化
Yulei Zhao1, Yonina R Murciano-Goroff2, Jenny Y Xue1,3
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer, New York, NY, USA.
Nature
|November 11, 2021
概括
肺癌中对KRAS (G12C) 抑制剂的耐药性可以通过新的KRAS,NRAS或BRAF突变出现. 向ERK信号可以克服这种获得的耐药性,建议结合疗法以改善患者的结果.
科学领域:
- 癌症学
- 分子生物学
- 遗传学
背景情况:
- KRAS (G12C) 抑制剂在肺癌中表现出适度的疗效,但耐药性机制尚不清楚.
- 了解耐药性对于改善针对性治疗患者的结果至关重要.
研究的目的:
- 研究肺癌患者对KRAS (G12C) 抑制剂的遗传性基础.
- 确定克服对KRAS (G12C) 向治疗的潜在策略.
主要方法:
- 对43名接受索托拉西布治疗的患者治疗前和治疗后瘤样本的分析.
- 在临床前耐药性研究中使用患者衍生的异种移植和细胞系模型.
- 使用单细胞测序来分析细胞水平的抵抗机制.
主要成果:
- 在27名患者中发现了治疗引起的KRAS,NRAS,BRAF和其他基因的改变.
- 临床前模型显示与二次RAS和/ 或BRAF突变相关的耐药性,绕过KRAS (G12C) 抑制.
- 在耐药模型中,ERK信号中间体的共同向增强了抗扩散效应.
结论:
- 对KRAS (G12C) 抑制剂的获得性耐药性是由多种基因变异驱动的,包括二次RAS/ BRAF突变.
- 针对ERK信号的组合策略可以克服获得的阻力.
- 需要进行进一步的临床试验,以在更广泛的患者群体中评估这些发现.
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