Systems Pharmacology Dissection of Cholesterol Regulation Reveals Determinants of Large Pharmacodynamic Variability between Cell Lines
Systems Pharmacology Dissection of Cholesterol Regulation Reveals Determinants of Large Pharmacodynamic Variability between Cell Lines
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DOI：
10.1016/j.cels.2017.11.002
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发表时间：
2017-12-27
期刊：
影响因子：
9.3
通讯作者：
Aebersold, Ruedi
中科院分区：
文献类型：
--
作者：
Blattmann, Peter;Henriques, David;Aebersold, Ruedi
在个体中，异质性药物反应表型是由剂量、药物特异性、遗传背景和环境因素的复杂相互作用引起的，因此挑战了我们对潜在过程的理解和药物在临床环境中的最佳使用。在这里，我们使用基于质谱的分子反应表型的定量和逻辑建模来解释一组细胞系中的药物反应差异。我们将这种方法应用于细胞胆固醇调节，这是一种具有高度临床意义的生物学过程。从各种靶向药理学或遗传治疗引起的量化分子表型，我们生成了细胞系特异性模型，该模型量化了独特型细胞内药物反应下的过程。这些模型显示，除了药物摄取和代谢外，进一步的细胞过程在细胞系之间显示出显著的药效学反应变异性，导致细胞系特异性药物反应表型。这项研究表明了将不同类型的定量系统水平的分子测量与建模相结合的重要性，以了解药理学扰动对复杂生物过程的影响。
In individuals, heterogeneous drug-response phenotypes result from a complex interplay of dose, drug specificity, genetic background, and environmental factors, thus challenging our understanding of the underlying processes and optimal use of drugs in the clinical setting. Here, we use mass-spectrometry-based quantification of molecular response phenotypes and logic modeling to explain drug-response differences in a panel of cell lines. We apply this approach to cellular cholesterol regulation, a biological process with high clinical relevance. From the quantified molecular phenotypes elicited by various targeted pharmacologic or genetic treatments, we generated cell-line-specific models that quantified the processes beneath the idiotypic intracellular drug responses. The models revealed that, in addition to drug uptake and metabolism, further cellular processes displayed significant pharmacodynamic response variability between the cell lines, resulting in cell-line-specific drug-response phenotypes. This study demonstrates the importance of integrating different types of quantitative systems-level molecular measurements with modeling to understand the effect of pharmacological perturbations on complex biological processes.