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长非编码RNA LRTOR通过促进YAP正反循环来驱动非小细胞肺癌中 osimertinib 的耐药性

Zhimin Miao¹, Zhou Sha², Jianzhong He³

¹State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR 999078, China; Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR 999078, China.

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概括

一种新的长非编码RNA,LRTOR,通过稳定YAP.通过稳定EGFR突变肺癌中驱动 osimertinib 耐药性. 向LRTOR可能会恢复非小细胞肺癌患者对奥西默蒂尼布的敏感性.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
遗传学是一个遗传学.

背景情况:

获得的耐药性限制了osimertinib (OSI) 在EGFR突变肺癌中的疗效.
非小细胞肺癌 (NSCLC) 的OSI耐药性背后的机制尚未完全理解.

研究的目的:

确定推动NSCLC中OSI耐药性的新机制.
研究长非编码RNAs (lncRNAs) 在OSI耐药性中的作用.
探索LRTOR作为克服OSI抵抗的潜在治疗目标.

主要方法:

对临床数据的分析,以将LRTOR表达与患者预后相关联.
在体外和体外功能研究,以评估LRTOR对瘤生长和OSI耐药性的影响.
涉及YAP,LATS,KCMF1和YAP/TEAD1复合体形成的机制研究.
在患者衍生器官异种移植模型中,siRNA介导的LRTOR的耗尽.

主要成果:

较高的LRTOR表达与OSI耐性NSCLC患者的预后不佳有关.
LRTOR促进瘤生长,并赋予OSI耐药性.
通过防止LATS介导的酸化和降解,LRTOR稳定了YAP.
LRTOR增强了YAP核转移和YAP/TEAD1复合体的形成,创造了一个积极的反循环.
在耐性NSCLC模型中,LRTOR耗尽恢复OSI灵敏度.

结论:

LRTOR是EGFR突变NSCLC中获得的奥西默提尼布耐药性的关键驱动因素.
LRTOR/YAP信号轴代表了OSI阻力的一种新机制.
LRTOR是克服肺癌中获得的OSI耐药性的有希望的治疗和预后标.

关键词:

长的非编码RNA是什么?非小细胞肺癌是非小细胞肺癌.奥西默提尼布的耐药性是的 - 相关蛋白质.

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