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通过有效的PI3Kinase向,绕过Nrf2过度激活的头癌中西斯普拉丁耐药性的治疗

Pedram Yadollahi¹, Kelli A McCord², Yang Li¹

¹Bobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA.

British journal of cancer

|October 6, 2025

概括

一种新的PI3K抑制剂,格达托利西布,显示出治疗抗化疗辐射的头支状细胞癌 (HNSCC) 的前景. 它有效地绕过Nrf2通路抵抗,抑制瘤生长,并在临床前模型中改善抗瘤免疫力.

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:

头部和部状细胞癌 (HNSCC) 通常会对标准的西斯和辐射疗法产生抗性,导致结果不佳.
Nrf2通路的过度激活有助于这种耐药性,并抑制抗瘤免疫力.
向疗法可以克服HNSCC的耐药性,特别是当与其他瘤驱动因素 (如NOTCH1突变) 相结合时.

研究的目的:

调查PI3K抑制剂吉达托利西布能否克服头角状细胞癌 (HNSCC) 中的Nrf2介导的耐药性.
在临床前的HNSCC模型中探索格达托利西布疗效的机制基础.

主要方法:

利用先进的机械学,代谢学和空间转录学方法.
采用HNSCC的临床前模型,包括以为基础的化学疗法在体内的shRNA查.
测试了新型PI3K抑制剂gedatolisib的疗效.

主要成果:

PI3K通路被激活在Nrf2驱动的,抗西斯普拉丁的HNSCC中,是可行的治疗标.
盖达托利西布通过诱导自,G2/M细胞循环停止和衰老来证明其有效性,同时破坏脂肪酸代谢.
在人性化的小鼠模型中,基达托利西布抑制了瘤在正位体和转移环境中的生长,减少了瘤缺氧,并减少了调节性T淋巴细胞透.

结论:

PI3K-AKT-mTOR通路在抗化学辐射的HNSCC中起着至关重要的作用.
像吉达托利西布这样的PI3K抑制剂代表了对常规治疗耐火性HNSCC的有前途的治疗策略.

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