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准ATR以克服肝细胞母细胞瘤中西斯普拉丁耐药性

Pierre Morel-Ribeiro¹, Marianna Cornet¹, Jill Pilet¹

¹Centre de Recherche des Cordeliers, Inserm, Université Paris Cité, Sorbonne Université, F-75006 Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, Labex Onco-Immunology, Institut du Cancer Paris CARPEM, AP-HP, F-75015 Paris, France.

Journal of hepatology

|December 1, 2025

概括

用elimusertib阻断ATR与思柏林协同作用,以克服肝细胞瘤 (HB) 中的思柏林耐药性. 这种组合在各种HB模型中显示出显著的临床前疗效,为儿科肝癌提供了一个有前途的新疗法策略.

科学领域:

儿科瘤学儿科瘤学
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:

肝母细胞瘤 (HB) 是最常见的儿科肝癌.
基于西斯普拉丁的化疗可以治愈大多数患者,但耐药性是一个重大挑战.
对于对西斯抗性HB的新型治疗策略有极大需求.

研究的目的:

为了确定对抗西斯普拉丁抗性肝细胞瘤的新疗法选择.
为了调查ATR在HB中介性抗性中介性抗性的作用.
为了评估ATR抑制剂与西斯普拉丁结合的疗效.

主要方法:

对14个HB细胞系和1个HCC细胞系进行分子分析.
在体外对101种化合物和58种组合进行查.
在患者衍生的HB培养物和球状模型中验证.
在异种移植和MYC驱动的HB样模型中的体内疗效研究.
机理学研究包括转录学和DNA损伤测试.

主要成果:

乙型肝炎细胞系表现出抗西斯普拉丁的特征,与上调的DNA修复途径有关.
鉴定出ATR是克服化疗抵抗的关键目标.
ATR抑制剂elimusertib在体外和体内与思丁表现出强烈的协同作用.
该组合通过增强的DNA损伤和p53激活诱导瘤细胞死亡.
此外,elimusertib与其他HB化疗药物协同作用,并抑制了mTOR.

结论:

在肝细胞瘤中,ATR在调解青抗性方面发挥着至关重要的作用.
埃利穆塞尔蒂布和西斯普拉丁的组合显示出显著的临床前疗效.
这种组合代表了对抗西斯普拉丁抗性HB的有前途的治疗方法.
需要对这种组合进行进一步的临床评估.

关键词:

这是一种ATR抑制剂.化学抗药性化学抗药性是一种抗药性.西斯普拉丁 (Cisplatin) 是一种在 Elimusertib 中使用.肝炎母细胞瘤是什么?协同效应是一种协同效应.

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