Omics-Based Interaction Framework – a systems model to reveal molecular drivers of synergy

Abstract

26Bioactive molecule library screening strategies may empirically identify effective combination therapies. 27However, without a systems theory to interrogate synergistic responses, the molecular mechanisms 28 underlying favorable drug-drug interactions remain unclear, precluding rational design of combination 29 therapies. Here, we introduce Omics-Based Interaction Framework (OBIF) to reveal molecular drivers 30 of synergy through integration of statistical and biological interactions in supra-additive biological 31 responses. OBIF performs full factorial analysis of feature expression data from single vs. dual factor 32 exposures to identify molecular clusters that reveal synergy-mediating pathways, functions and 33 regulators. As a practical demonstration, OBIF analyzed a therapeutic dyad of immunostimulatory small 34 molecules that induces synergistic protection against influenza A pneumonia. OBIF analysis of 35 transcriptomic and proteomic data identified biologically relevant, unanticipated cooperation between 36 RelA and cJun that we subsequently confirmed to be required for the synergistic antiviral protection. To 37 demonstrate generalizability, OBIF was applied to data from a diverse array of Omics platforms and 38 experimental conditions, successfully identifying the molecular clusters driving their synergistic 39 responses. Hence, OBIF is a phenotype-driven systems model that supports multiplatform exploration 40 of synergy mechanisms. 41 42 Keywords 43 Data integration / Inducible epithelial resistance / Multi-Omics / Pneumonia / Synergy 44 45 Subject Categories