同时准JAK1/STAT6/GAS6/TAM信号,提高了Ewing肉瘤的化疗疗效率
Le Yu1,2, Yu Deng1,2, Xiaodong Wang1,3
1Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Nature communications
|June 21, 2024
概括
尤文肉瘤化学抵抗涉及化学疗法激活的TAM激酶. 抑制JAK1或TAM激酶使瘤对治疗重新敏感,为这种儿科癌症提供了新的治疗策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症治疗方法 癌症治疗方法
背景情况:
- 尤文肉瘤是一种儿科骨和软组织癌症.
- 高复发率 (~50%) 是由于化疗耐药性而发生的.
- 目前的治疗方法包括化疗,放射和手术.
研究的目的:
- 研究Ewing肉瘤中化疗耐药性的机制.
- 确定克服化疗抵抗的新疗法目标.
- 评估抑制特定酶通路的有效性.
主要方法:
- 尤文肉瘤细胞的基蛋白质分析.
- 对Akt,ERK和JAK1/STAT6信号通路的评估.
- 使用药理抑制剂 (filgotinib,UNC2025,MRX-2843) 的体外和体内研究.
主要成果:
- 化疗激活TAM (TYRO3,AXL,MERTK) 激酶,增强Akt/ERK信号传递并促进化疗抵抗.
- 化疗通过伪激酶域释放诱导JAK1的激活,导致GAS6的分泌.
- 抑制JAK1或TAM激酶使尤宁肉瘤对化疗敏感.
- 一种TAM激酶抑制剂MRX-2843,在体内显著提高化疗疗效率.
结论:
- 确定了一种涉及JAK1介导的TAM激酶激活在尤宁肉瘤中的新型化学抵抗途径.
- 向JAK1或TAM激酶是一个有前途的治疗策略.
- 对TAM激酶的药理抑制显示了对Ewing肉瘤治疗的翻译潜力.
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