The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies.
The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies.
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DOI：
10.7554/elife.52707
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发表时间：
2020-09-18
期刊：
影响因子：
7.7
通讯作者：
Stolovitzky G
中科院分区：
文献类型：
--
作者：
Diaz JE;Ahsen ME;Schaffter T;Chen X;Realubit RB;Karan C;Califano A;Losic B;Stolovitzky G
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其组合的转录反应了解不够。我们分析了用单一药物及其组合治疗的细胞的匹配时间过程 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。基因调控网络中转录因子的及时连续激活被牵涉其中。这种转录级联的性质表明，当两种不相关的个体药物引起的转录反应相关时，可能会产生药物协同作用。我们使用这些结果作为简单预测算法的基础，在独立数据集中预测协同药物组合时，AUROC 达到 0.77。
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.