Quantifying ERK-activity in response to inhibition of the BRAFV600E-MEK-ERK cascade using mathematical modelling
Quantifying ERK-activity in response to inhibition of the BRAFV600E-MEK-ERK cascade using mathematical modelling
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使用数学模型量化对 BRAFV600E-MEK-ERK 级联抑制的 ERK 活性
DOI：
10.1101/2021.04.20.440559
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Hamis S
中科院分区：
文献类型：
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作者：
Hamis S
背景同时抑制BRAF-MEK-ERK级联的多个组分（垂直抑制）已成为治疗BRAF突变型黑色素瘤的标准治疗方法。然而，垂直抑制如何协同抑制细胞内ERK活性的分子机制，因此细胞增殖，尚未完全elucidate.MethodsWe开发一个机械的数学模型，描述了如何突变BRAF抑制剂，达拉非尼，和MEK抑制剂，曲美替尼，影响BRAFV 600 E-MEK-ERK信号。该模型是基于一个系统的化学反应，描述级联信号动力学。使用质量作用动力学，化学反应被重新表示为常微分方程，参数化的体外数据和数值求解，以获得级联组件concentrationsResultsThe模型的时间演变提供了一种定量的方法来计算如何达拉非尼和曲美替尼可以用于联合协同抑制ERK活性BRAFV 600 E-突变型黑色素瘤细胞。该模型阐明了BRAFV 600 E-MEK-ERK级联的垂直抑制的分子机制，并描绘了升高的BRAF浓度如何产生对达拉非尼和曲美替尼的耐药性。计算模拟进一步表明，ATP水平升高可能是一个因素，在药物耐药性dabrafenib.ConclusionsThe模型可用于系统地激励哪些dabrafenib-trametinib剂量组合，用于治疗BRAFV 600 E突变的黑色素瘤，值得实验研究。
BackgroundSimultaneous inhibition of multiple components of the BRAF-MEK-ERK cascade (vertical inhibition) has become a standard of care for treating BRAF-mutant melanoma. However, the molecular mechanism of how vertical inhibition synergistically suppresses intracellular ERK activity, and consequently cell proliferation, are yet to be fully elucidated.MethodsWe develop a mechanistic mathematical model that describes how the mutant BRAF inhibitor, dabrafenib, and the MEK inhibitor, trametinib, affect BRAFV600E-MEK-ERK signalling. The model is based on a system of chemical reactions that describes cascade signalling dynamics. Using mass action kinetics, the chemical reactions are re-expressed as ordinary differential equations that are parameterised by in vitro data and solved numerically to obtain the temporal evolution of cascade component concentrations.ResultsThe model provides a quantitative method to compute how dabrafenib and trametinib can be used in combination to synergistically inhibit ERK activity in BRAFV600E-mutant melanoma cells. The model elucidates molecular mechanisms of vertical inhibition of the BRAFV600E-MEK-ERK cascade and delineates how elevated BRAF concentrations generate drug resistance to dabrafenib and trametinib. The computational simulations further suggest that elevated ATP levels could be a factor in drug resistance to dabrafenib.ConclusionsThe model can be used to systematically motivate which dabrafenib–trametinib dose combinations, for treating BRAFV600E-mutated melanoma, warrant experimental investigation.