突变RIT1与YAP合作,驱动一个类似于EMT的肺癌状态
Mary C Rominger1, Saksham Gupta1, Sitapriya Moorthi1
1Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109.
bioRxiv : the preprint server for biology
|November 28, 2024
概括
研究人员开发了一种针对RIT1突变肺癌的新老鼠模型. 该模型显示,RIT1与Nf2损失合作,驱动侵袭性癌症,提供新的治疗点,如TEAD.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 遗传学 遗传学 是一个
背景情况:
- 瘤基因成已经为肺腺癌产生了向治疗方法,但RIT1突变仍然未被向.
- RIT1突变是约2%的肺腺癌的驱动事件,与KRAS和EGFR突变独立发生.
- 缺乏临床前模型阻碍了RIT1突变肺癌的治疗开发.
研究的目的:
- 建立一种针对RIT1驱动的肺癌的新型小鼠模型.
- 调查RIT1与其他遗传变异之间的致癌合作.
- 为了确定RIT1突变肺癌的潜在治疗点.
主要方法:
- 创建了一个CRE调节的小鼠模型,用于诱导人类RIT1 M90I变体的表达.
- 评估了单独RIT1 M90I表达的癌症发展,p53损失,以及Nf2无活化.
- 分析了下游的信号通路,包括cJUN和YAP/TEAD.
- 在体内评估MEK和YAP/TEAD抑制剂的治疗疗效.
主要成果:
- 单独或与p53损失的RIT1 M90I显示出弱的致癌潜力.
- RIT1 M90I和Nf2无活化之间的协同作用导致了具有迅速发病的侵袭性,高度透的肺癌.
- 瘤合作是由cJUN的协同激活介导的.
- 抑制MEK和YAP/TEAD通路抑制了RIT1驱动的肺癌生长.
结论:
- 通过cJUN激活,RIT1 M90I与Nf2无活化合作,通过cJUN激活驱动侵略性肺癌.
- YAP/TEAD信号是RIT1致癌活性的一个关键媒介.
- 在RIT1突变肺癌中,TEAD是一个有前途的治疗标.
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