针对mTOR途径调节不同EGFR突变的NSCLC中铁亡的机制
Chunjiao Wu1, Rui Zhong2,3, Tianxue Wei4
1Phase I Clinical Research Ward, Jilin Cancer Hospital, Changchun, Jilin 130000, P.R. China.
Oncology letters
|May 16, 2024
概括
非小细胞肺癌 (NSCLC) 的耐药性可以通过向ferroptosis来克服. 抑制mTOR途径诱导EGFR耐药和野生型NSCLC细胞中的铁亡,提供新的治疗策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 患有表皮生长因子受体 (EGFR) 激活突变的非小细胞肺癌 (NSCLC) 患者可以从EGFR-铁氨酸激酶抑制剂 (TKI) 中受益.
- 对EGFR-TKI的耐药性是一个重大的临床挑战,需要新的治疗方法.
- 铁亡是一种受调节的细胞死亡途径,正在成为克服NSCLC药物耐药性的有希望的策略.
研究的目的:
- 研究不同类型的EGFR突变NSCLC中铁亡调节的作用和机制.
- 探索向猛素 (mTOR) 途径向哺乳动物点的潜力,以诱导铁亡并克服耐药性.
主要方法:
- 使用的NSCLC细胞系:H1975 (EGFR T790M/L858R突变),A549 (EGFR野生型) 和H3255 (EGFR L858R突变).
- 通过西部涂抹和RT-qPCR评估铁灭症标志物.
- 测量了细胞活力 (MTT测定),反应性氧物种 (ROS) 水平 (流细胞计) 和脂质过氧化 (MDA水平).
主要成果:
- 与野生类型/敏感突变细胞相比,EGFR耐药突变细胞对铁灭诱导剂埃拉斯的敏感性增加.
- mTOR抑制剂everolimus (RAD001) 诱导了剂量依赖的细胞死亡,这种细胞死亡在耐药和野生类型细胞中被ferrostatin-1逆转,但不是敏感的细胞.
- 与埃拉斯结合的RAD001在EGFR耐药和野生型NSCLC细胞中更有效. 高剂量的RAD001降低了与铁死相关的蛋白质 (FTH1,GPX4,费罗波丁),并增加了ROS和MDA水平.
结论:
- 抑制mTOR通路降低了与铁亡相关的蛋白质的调节,并增加了EGFR耐药和野生型NSCLC细胞中的氧化应激标记物 (ROS,MDA).
- 向mTOR途径可以诱导铁亡,这是克服NSCLCEGFR-TKI耐药性的潜在策略.
- 对诱导铁亡的mTOR抑制的进一步研究对新型NSCLC治疗有希望.
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