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达拉克森拉西布 (RMC-6236) 是一种有效的针对性治疗RAS突变神经母细胞瘤的疗法

Ronald D Hill, Krista M Dalton, Richard Kurupi

bioRxiv : the preprint server for biology

|February 27, 2026

概括

达拉克森拉西布 (RMC-6236) 通过抑制MAPK通路,有效地向RAS突变神经母细胞瘤 (NB). 这种新疗法在临床前模型中显示出降低瘤生长和改善存活率的前景.

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:

神经母细胞瘤 (NB) 是一个常见的儿童脑外固体瘤,在复发性/耐药性高风险 (HR) 病例中表现不佳.
激活RAS-MAPK通路突变在HRNB中很常见,但现有的向疗法已显示出有限的疗效.
达拉克森拉西布 (RMC-6236) 是一种RAS(ON) 抑制剂,在具有RAS突变的成年癌症中表现出活性.

研究的目的:

在具有RAS通路激活的神经母细胞瘤模型中评估Daraxonrasib (RMC-6236) 的治疗疗效.
在这些模型中研究RMC-6236对瘤信号的调制.

主要方法:

在神经母细胞瘤细胞系和携带RAS或NF1突变的小鼠模型中对RMC-6236的临床前评估.
细胞活力的评估,MAPK信号抑制,BIM和BCL-2表达,以及BIM:BCL-2复合体的形成.
用BCL-2抑制剂venetoclax进行组合治疗的研究.

主要成果:

在RAS突变和NF1突变NB模型中,RMC-6236显著降低了细胞活力,抑制了MAPK信号传递,并增加了细胞死亡.
在体内研究表明RMC-6236的目标活性,减少瘤生长和延长RAS突变HRNB小鼠模型的生存期.
RMC-6236诱导了BIM和BCL-2的上调,而venetoclax通过破坏BIM:BCL-2复合体来增强了RMC-6236介导的细胞杀死.

结论:

达拉克森拉西布 (RMC-6236) 是针对RAS突变神经母细胞瘤的合理向疗法,这是与不良结果相关的子集.
RMC-6236有效地向神经母细胞瘤中的MAPK通路,并保证扩展临床研究.
与venetoclax的联合治疗可能进一步提高RMC-6236治疗的神经母细胞瘤的治疗疗效.

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