流体衍生的NRG1使得瘤性KRAS绕道在胰腺癌中
Jincheng Han1, Jiaqian Xu2, Yonghong Liu1
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 USA.
Genes & development
|September 29, 2023
概括
癌症相关纤维细胞 (CAF) 通过激活NRG1信号来促进胰腺癌中对KRAS抑制剂的耐药性. 针对这种途径可以克服耐药性,并提高胰腺管道腺癌 (PDAC) 患者的治疗疗效.
科学领域:
- 在瘤学瘤学.
- 癌症生物学 癌症生物学
- 分子治疗学分子治疗学
背景情况:
- 激活KRAS突变 (KRAS*) 是胰腺管腺癌 (PDAC) 增长和代谢的关键驱动因素.
- 克拉斯*抑制剂最初显示出有效性,但由于抵抗机制,瘤经常复发.
研究的目的:
- 研究癌症相关纤维细胞 (CAFs) 在PDAC中调解对KRAS*抑制剂的耐药性的作用.
- 为了确定CAFs对KRAS*抑制剂绕行产生贡献的特定分子通路.
主要方法:
- 使用了人类和小鼠PDAC模型.
- 研究了基因和药理抑制KRAS*,ERBB2/3和NRG1.3的效应.
- 评估了组合疗法的协同效应.
主要成果:
- 克拉斯*抑制可以提高癌细胞中ERBB2和ERBB3的表达.
- 癌细胞通过ERBB2/3信号利用CAF衍生的NRG1进行KRAS*独立生长.
- 抑制ERBB2/3或NRG1消除了KRAS*绕道,并与KRAS*抑制剂协同作用.
结论:
- 在PDAC中,CAFs通过近性NRG1/ERBB2/3信号传递促进KRAS*抑制剂耐药性.
- 针对CAF-NRG1-ERBB2/3轴是一种可行的治疗策略,可以提高KRAS*抑制剂在PDAC中的疗效.
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