The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies

Our ability to predict the effects of drug combinations is limited, in part by limited understanding of how the transcriptional response of two monotherapies results in that of their combination. We performed the first analysis of matched time course RNAseq profiling of cells treated with both single drugs and their combinations. The transcriptional signature of the synergistic combination we studied had unique gene expression not seen in either constituent monotherapy. This can be explained mechanistically by the sequential activation of transcription factors in time in the gene regulatory network. 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. RNAseq of MCF7 and LNCaP cells each treated with DMSO, 3 drugs, and the 3 combinations of the 3 drugs, in triplicate, well as a triple combination in LNCaP, at 0, 3, 6, 9, 12, and 24 hours