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The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies
eLife ( IF 7.7 ) Pub Date : 2020-09-18 , DOI: 10.7554/elife.52707
Jennifer El Diaz 1, 2, 3 , Mehmet Eren Ahsen 1, 3, 4 , Thomas Schaffter 1, 3 , Xintong Chen 1 , Ronald B Realubit 5, 6 , Charles Karan 5, 6 , Andrea Califano 5, 7, 8, 9 , Bojan Losic 1, 10, 11, 12 , Gustavo Stolovitzky 1, 3, 5, 7
Affiliation  

Our ability to discover effective drug combinations is limited, in part by insufficient understanding of how the transcriptional response of two monotherapies results in that of their combination. We analyzed matched time course RNAseq profiling of cells treated with single drugs and their combinations and found that the transcriptional signature of the synergistic combination was unique relative to that of either constituent monotherapy. The sequential activation of transcription factors in time in the gene regulatory network was implicated. The nature of this transcriptional cascade suggests that drug synergy may ensue when the transcriptional responses elicited by two unrelated individual drugs are correlated. We used these results as the basis of a simple prediction algorithm attaining an AUROC of 0.77 in the prediction of synergistic drug combinations in an independent dataset.

中文翻译:

细胞对药物组合的转录组反应大于对单一疗法的反应总和

我们发现有效药物组合的能力是有限的,部分原因是对两种单一疗法的转录反应如何导致它们组合的转录反应的了解不足。我们分析了用单一药物及其组合处理的细胞的匹配时程 RNAseq 分析,发现协同组合的转录特征相对于任一成分单一疗法的转录特征是独特的。涉及基因调控网络中转录因子的顺​​序激活。这种转录级联的性质表明,当由两种不相关的单个药物引起的转录反应相关时,可能会出现药物协同作用。我们将这些结果用作实现 AUROC 为 0 的简单预测算法的基础。
更新日期:2020-09-18
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