Exploration of Target Synergy in Cancer Treatment by Cell-Based Screening Assay and Network Propagation Analysis

Computational approaches have previously been introduced to predict compounds with activity against multiple targets or compound combinations with synergistic functional effects. By contrast, there are no computational studies available that explore combinations of targets that might act synergistically upon small molecule treatment. Herein, we introduce an approach designed to identify synergistic target pairs on the basis of cell-based screening data and compounds with known target annotations. The targets involved in forming synergistic pairs were analyzed through a novel network propagation algorithm for rationalizing possible common synergy mechanisms. This algorithm enabled further analysis of each synergistic target pair and the identification of "interactors", i.e., proteins with higher propagation scores than would be expected by adding the individual contributions of each target in the synergistic pair. We detected 137 synergistic target pairs including 51 unique targets. A global network analysis of these 51 targets made it possible to derive a subnetwork of proteins with significant synergy. Furthermore, interactors were identified for 87 synergistic target pairs upon individual analysis of the network propagation of each pair. These interactors were associated with pathways related to cancer and apoptosis, membrane transport, and steroid metabolism and provided possible explanations of synergistic effects.