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克服奥西默提尼布耐药性的新方法是使用布罗姆多马因和额外终端域抑制剂

Yosuke Miyashita^1,2, Ken Tajima^1,2, Kenta Izumi^1,2

¹Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.

|March 4, 2025

概括

这项研究表明,纤维细胞生长因子1 (FGF1) 通过改变染色素,在肺癌中驱动对奥西默蒂尼布的耐药性. 将代抑制剂与奥西默蒂尼布结合起来,可以克服这种抗药性,提供一种新的治疗策略.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.

背景情况:

奥西默提尼布是EGFR突变肺癌的第一线治疗方法,但耐药性机制尚未完全理解.
人们怀疑在耐药性方面存在表观遗传失调,但具体的途径尚不清楚.

研究的目的:

调查表观遗传学在肺癌中 osimertinib 耐药性的作用.
探索向表观遗传修饰的治疗潜力,以克服 osimertinib 耐药性.

主要方法:

已确立的耐奥西默提尼布的肺癌细胞系.
通过测序 (ATAC-seq) 和RNA测序来分析染色质的可访问性和基因表达,利用了转化酶可访问性染色质的测试.
研究了纤维细胞生长因子1 (FGF1) 和基因素修饰的作用.
在体外和体内测试了与马丁和外终域 (BET) 抑制剂和奥西默提尼布的组合疗法.

主要成果:

在耐药细胞中观察到染色质可访问性的显著变化.
鉴定出FGF1是一种通过基因组修饰来调节的抗性相关基因.
过度表达FGF1诱导了奥西默提尼布耐药性,而其抑制减弱了耐药性.
结合BET抑制剂和奥西默提尼布的联合治疗有效地克服了细胞系和老鼠异种移植模型中的抗性.
在临床奥西默提尼布耐药样本中发现FGF1表达的增加.

结论:

表观遗传变化,特别是涉及调节FGF1的基因组修饰,在奥西默蒂尼布耐药性中起着至关重要的作用.
通过BET抑制剂向激素修饰是克服肺癌中奥西默提尼布耐药性的有希望的新策略.
FGF1是一种潜在的治疗点,可以克服异星丁尼抗药性.

关键词:

在ATAC-seqq中使用.表观基因组学是指表观基因组学.一个FGF1的FGF1.肺部瘤是什么肺部瘤奥西米尔丁尼布 (osimertinib) 是一种

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