对小分子抑制TEAD调节的转录机制的抵抗机制的识别
Aishwarya Kulkarni1,2, Varshini Mohan1, Tracy T Tang3
1Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
EMBO reports
|August 5, 2024
概括
这项研究揭示了Hippo,MAPK和JAK-STAT通路中的突变会影响癌细胞对TEAD抑制剂的反应. 结合TEAD和MEK抑制剂,可以协同阻止癌细胞的增殖和瘤的生长.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症遗传学 癌症遗传学
背景情况:
- 河马通路调节YAP/TAZ转录因子,对于细胞生长和癌症至关重要.
- 针对YAP/TEADs的小分子抑制剂正在临床试验中,用于与Hippo通路放松调节的癌症,如半质瘤.
- 了解对这些抑制剂的抵抗机制对于有效的癌症治疗至关重要.
研究的目的:
- 为了确定调节美索瘤细胞系对TEAD棕化抑制剂反应的遗传因素.
- 阐明抗 TEAD 抑制的抵抗机制.
- 探索用于增强抗瘤活性的组合疗法.
主要方法:
- 在中皮质瘤细胞系中进行全基因组的CRISPR/Cas9查.
- 在突变细胞系中分析基因表达程序.
- 在体外增殖测定和体内异种移植研究.
主要成果:
- 在Hippo,MAPK和JAK-STAT通路中的突变会影响对TEAD抑制剂的反应.
- 过度激活MAPK通路通过重新激活YAP/TAZ目标基因来赋予耐药性.
- 联合抑制TEAD和MEK在间皮瘤和肺癌模型中协同降低了扩散和瘤生长.
结论:
- 激活MAPK通路是对TEAD抑制剂耐药性的关键机制.
- 与TEAD和MEK抑制剂的联合治疗显示出显著的抗瘤潜力.
- 这些发现提供了克服耐药性的策略,并改进了针对Hippo通路的癌症疗法.
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