在胰腺癌中,NFAT5控制了细胞可塑性驱动的对KRAS向治疗的耐药性
Daiyong Deng1,2, Habeebunnisa Begum1,2, Tong Liu1,2
1Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University New Jersey Medical School, Newark, NJ, USA.
The Journal of experimental medicine
|October 21, 2024
概括
慢性胰腺炎通过TGFβ诱导的EMT促进胰腺癌中KRAS治疗的耐药性. 准核因子NFAT5 (激活T细胞的核因子5) 可以克服这种抵抗并提高生存率.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 免疫学 免疫学 免疫学
背景情况:
- 胰腺管道腺癌 (PDAC) 表现出对KRAS治疗的耐药性,通常与细胞可塑性有关,如上皮细胞转化为介质细胞转化 (EMT).
- 慢性胰腺炎是PDAC的危险因素,在瘤微环境 (TME) 中增加转化生长因子β (TGFβ),导致治疗耐药性.
研究的目的:
- 研究TGFβ信号驱动PDAC中的KRAS治疗耐药性的分子机制.
- 确定克服PDAC中抗性的新型治疗点.
主要方法:
- 对参与TGFβ信号传递的蛋白质复合物的分析.
- 在临床前模型中抑制NFAT5.
- 评估巨细胞的招募和功能.
主要成果:
- TGFβ诱导SMAD3/SMAD4/NFAT5复合体,通过S100A4激活促进EMT和抵抗.
- 在小鼠中,NFAT5抑制降低了胰腺炎诱导的KRAS耐药性和改善了生存率.
- 由TGFβ刺激的CCL2分泌物招募了巨细胞,有助于KRAS绕过.
结论:
- 在PDAC中,TGFβ信号传递在EMT驱动的KRAS治疗耐药性中起着至关重要的作用.
- NFAT5是一种可用药物的目标,可以破坏抗药网络,为增强PDAC治疗提供了潜在的战略.
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