DeSigN: connecting gene expression with therapeutics for drug repurposing and development.
DeSigN: connecting gene expression with therapeutics for drug repurposing and development.
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DOI：
10.1186/s12864-016-3260-7
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发表时间：
2017-01-25
期刊：
影响因子：
4.4
通讯作者：
Cheong SC
中科院分区：
文献类型：
--
作者：
Lee BK;Tiong KH;Chang JK;Liew CS;Abdul Rahman ZA;Tan AC;Khang TF;Cheong SC
药物发现和开发管道是一个漫长而艰巨的过程，不可避免地阻碍了药物的快速开发。因此，迫切需要提高药物开发效率的策略，使有效的药物进入临床。精密医学已经证明，癌细胞的遗传特征可以用来预测药物反应，并且新出现的证据表明，通过同时探索许多基因的累积效应，可以更准确地预测基因-药物之间的联系。我们开发了DeSigN，一个基于网络的工具，用于使用基因表达模式预测药物对癌细胞系的疗效。该算法将来自差异表达基因的表型特异性基因特征与140种药物的药物反应数据（IC50）相关的预定义基因表达谱相关联。在四项已发表的GEO研究中，DeSigN成功预测了正确的药物敏感性结果。此外，该研究预测博舒替尼（一种Src/Abl激酶抑制剂）作为口腔鳞状细胞癌（OSCC）细胞系的敏感抑制剂。博舒替尼在OSCC细胞株的体外验证表明，这些细胞株对博舒替尼确实敏感，IC50为0.8 ~ 1.2 μM。作为进一步的证实，我们通过实验证明博舒替尼在OSCC细胞系中具有抗增殖活性，这表明DeSigN能够可靠地预测可能有利于肿瘤控制的药物。设计是一种强大的方法，可用于使用从基因表达分析中获得的输入基因特征来识别候选药物。这个用户友好的平台可以用来识别对感兴趣的癌细胞系具有意想不到功效的药物，因此可以用于药物的再利用，从而提高药物开发的效率。本文的在线版本（doi:10.1186/s12864-016-3260-7）包含补充材料，可供授权用户使用。
The drug discovery and development pipeline is a long and arduous process that inevitably hampers rapid drug development. Therefore, strategies to improve the efficiency of drug development are urgently needed to enable effective drugs to enter the clinic. Precision medicine has demonstrated that genetic features of cancer cells can be used for predicting drug response, and emerging evidence suggest that gene-drug connections could be predicted more accurately by exploring the cumulative effects of many genes simultaneously. We developed DeSigN, a web-based tool for predicting drug efficacy against cancer cell lines using gene expression patterns. The algorithm correlates phenotype-specific gene signatures derived from differentially expressed genes with pre-defined gene expression profiles associated with drug response data (IC50) from 140 drugs. DeSigN successfully predicted the right drug sensitivity outcome in four published GEO studies. Additionally, it predicted bosutinib, a Src/Abl kinase inhibitor, as a sensitive inhibitor for oral squamous cell carcinoma (OSCC) cell lines. In vitro validation of bosutinib in OSCC cell lines demonstrated that indeed, these cell lines were sensitive to bosutinib with IC50 of 0.8–1.2 μM. As further confirmation, we demonstrated experimentally that bosutinib has anti-proliferative activity in OSCC cell lines, demonstrating that DeSigN was able to robustly predict drug that could be beneficial for tumour control. DeSigN is a robust method that is useful for the identification of candidate drugs using an input gene signature obtained from gene expression analysis. This user-friendly platform could be used to identify drugs with unanticipated efficacy against cancer cell lines of interest, and therefore could be used for the repurposing of drugs, thus improving the efficiency of drug development. The online version of this article (doi:10.1186/s12864-016-3260-7) contains supplementary material, which is available to authorized users.