Integrative network and transcriptomics-based approach predicts genotype- specific drug combinations for melanoma.

Computational methods for drug combination predictions are needed to identify effective therapies that improve durability and prevent drug resistance in an efficient manner. In this paper, we present SynGeNet, a computational method that integrates transcriptomics data characterizing disease and drug z-score profiles with network mining algorithms in order to predict synergistic drug combinations. We compare SynGeNet to other available transcriptomics-based tools to predict drug combinations validated across melanoma cell lines in three genotype groups: BRAF-mutant, NRAS-mutant and combined. We showed that SynGeNet outperforms other available tools in predicting validated drug combinations and single agents tested as part of additional drug pairs. Interestingly, we observed that the performance of SynGeNet decreased when the network construction step was removed and improved when the proportion of matched-genotype validation cell lines increased. These results suggest that delineating functional information from transcriptomics data via network mining and genomic features can improve drug combination predictions.