Nature Chemical Biology的一篇新论文提出了一种全新的刻画药物作用机制的方式,用RNAi技术产生一系列细胞系,用药物对这些细胞系的“response signature”来反映药物对细胞的作用特征。通过与已知药物“response signature”的相似性搜索,可以预测和鉴定新药物的作用机制(mechanism of action)。(原文:A mammalian functional-genetic approach to characterizing cancer therapeutics)
之前,对药物的作用机制或作用靶标的刻画主要有两类方法:一为NCI 60,一为CMAP。对这两套思路的介绍可以参考我们论文中的这段描述:
"There are two methods which are commonly used to interrogate the action of compounds on cells. The first method, adopted by the Connectivity Map [19] effort, measures a ‘compound response signature.’ In this approach gene expression signatures are established based on changes in gene expression in response to short term treatment with particular compounds; this response signature can serve as an effective tool for probing the compound(s) mechanism of action (MOA) [19]. A second method is measurement of a ‘drug sensitivity signature’ and is used by various applications based on the National Cancer Institute NCI 60 in vitro drug screen project [20]. The NCI 60 cell lines screen panel has proved to be an effective way to identify drug sensitivity specific biomarkers [21] as the panel has already been comprehensively characterized via profiling at different levels (mRNA, protein, microRNAs, DNA methylation and metabolites etc.)". (全文链接:Pre-Clinical Drug Prioritization via Prognosis-Guided Genetic Interaction Networks,PLoS ONE 2010)
Nature Chemical Biology这篇文章中的方法大致类似NCI 60的思路,不同点在于:NCI 60是利用自然发生的60中细胞系作为维度,而这篇文章是选择跟细胞生长凋亡密切相关的若干基因(针对肿瘤药物的研究),产生针对性很强的一组细胞系。NCI 60系列与CMAP系列的最大区别在于前者内涵了表型phenotpype的信息,因此可以满足一些有针对性的任务(比如肿瘤药物筛选)。