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模拟BRAFV600E-MEK-ERK信号动态,以应对垂直抑制治疗策略

Alice De Carli¹, Yury Kapelyukh², Jochen Kursawe¹

¹School of Mathematics and Statistics, University of St Andrews, St Andrews, Scotland, UK.

NPJ systems biology and applications

|May 15, 2024

概括

通过模拟BRAFV600E-MEK-ERK途径抑制,开发数学模型有助于确定最佳的低剂量癌症疗法. 这种方法有助于找到有效的药物组合来治疗黑色素瘤.

科学领域:

在瘤学瘤学.
系统生物学系统生物学
药理学药理学是指药理学的学科.

背景情况:

垂直抑制针对细胞内通路的多个组成部分,如BRAFV600E-MEK-ERK通路,用于黑色素瘤治疗.
向疗法虽然有效,但面临着早期耐药性的挑战,促使研究复杂的低剂量策略.
在实验中设计和测试许多复杂的治疗策略往往是不可行的.

研究的目的:

开发一个BRAFV600E-MEK-ERK信号通路的定量数学模型.
模拟各种药物组合和剂量的作用,包括达布拉费尼布 (DBF),特拉美丁尼布 (TMT) 和SCH772984 (SCH).
减少有效治疗策略的搜索空间,并指导实验研究.

主要方法:

创建了一个BRAFV600E-MEK-ERK信号动态的数学模型.
药物与蛋白质的相互作用被转化为一种化学反应系统.
使用体外数据进行参数化,并通过质量作用定律转换为普通微分方程 (ODE).
对ODEs的数值解决方案,以模拟不同处理条件下的途径组件度随时间变化.

主要成果:

模拟探索了BRAFV600E-MEK-ERK通路的各种抑制剂组合和剂量.
该模型表明,达布拉费尼布 (DBF) 和三重疗法 (DBF-TMT-SCH) 对BRAFV600E度表现出显著的敏感性.
特拉美丁尼布 (TMT) 和SCH772984 (SCH) 单一疗法在中没有显示这种敏感性.

结论:

开发的数学模型有效地模拟了药物治疗下的细胞内信号通路动态.
该模型是确定BRAFV600E突变黑色素瘤有希望,复杂,低剂量治疗策略的宝贵工具.
在的结果突出了不同治疗方案对BRAFV600E水平的不同敏感性,指导了未来的研究.

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