TY - JOUR TI - The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies AU - Diaz, Jennifer EL AU - Ahsen, Mehmet Eren AU - Schaffter, Thomas AU - Chen, Xintong AU - Realubit, Ronald B AU - Karan, Charles AU - Califano, Andrea AU - Losic, Bojan AU - Stolovitzky, Gustavo A2 - Valencia, Alfonso A2 - Cheah, Kathryn Song Eng A2 - Flobak, Asmund VL - 9 PY - 2020 DA - 2020/09/18 SP - e52707 C1 - eLife 2020;9:e52707 DO - 10.7554/eLife.52707 UR - https://doi.org/10.7554/eLife.52707 AB - 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. KW - MCF7 KW - LNCaP KW - cancer biology KW - drug synergy KW - transcriptomics KW - rna-seq JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -