Interpreting the Mechanism of Synergism for Drug Combinations Using Attention-Based Hierarchical Graph Pooling

SIMPLE SUMMARY: This paper introduces a novel graph neural network (a hierarchical graph pooling model), SANEpool, to effectively detect core sub-networks of significant genes for predicting the synergy score of drug/drug combinations in cancer. SANEpool successfully addresses the limitations of the un-transparency in the prediction process of previous computational AI models for drug synergy prediction, while providing the superior predictive performance than popular baselines on numerous drug-synergy prediction datasets. The success of SANEpool indicates that significant gene-gene interactions and gene-drug interactions play a crucial role in designing powerful deep learning models to provide accurate prediction and to reveal the mechanism of the synergy (MoS). ABSTRACT: Synergistic drug combinations provide huge potentials to enhance therapeutic efficacy and to reduce adverse reactions. However, effective and synergistic drug combination prediction remains an open question because of the unknown causal disease signaling pathways. Though various deep learning (AI) models have been proposed to quantitatively predict the synergism of drug combinations, the major limitation of existing deep learning methods is that they are inherently not interpretable, which makes the conclusions of AI models untransparent to human experts, henceforth limiting the robustness of the model conclusion and the implementation ability of these models in real-world human–AI healthcare. In this paper, we develop an interpretable graph neural network (GNN) that reveals the underlying essential therapeutic targets and the mechanism of the synergy (MoS) by mining the sub-molecular network of great importance. The key point of the interpretable GNN prediction model is a novel graph pooling layer, a self-attention-based node and edge pool (henceforth SANEpool), that can compute the attention score (importance) of genes and connections based on the genomic features and topology. As such, the proposed GNN model provides a systematic way to predict and interpret the drug combination synergism based on the detected crucial sub-molecular network. Experiments on various well-adopted drug-synergy-prediction datasets demonstrate that (1) the SANEpool model has superior predictive ability to generate accurate synergy score prediction, and (2) the sub-molecular networks detected by the SANEpool are self-explainable and salient for identifying synergistic drug combinations.