Fusing Micro- and Macro-Scale Information to Predict Anticancer Synergistic Drug Combinations

Drug combination therapy is highly regarded in cancer treatment. Computational methods offer a time- and cost-effective opportunity to explore the vast combination space. Although deep learning-based prediction methods lead the field, their generalization ability remains unsatisfactory. Few previous studies have the ability to finely characterize drugs and cell lines at both the micro-scale and macro-scale. Furthermore, the interaction of cross-scale information is often overlooked. These two points limit models' ability of predicting the synergism of drug combinations in cell lines. To address the issues, we propose a novel anticancer synergistic drug combination prediction method termed MMFSynergy in this article. The construction of MMFSynergy involves three phases. First, MMFSynergy pretrains two micro encoders and a macro graph encoder, which can capture micro- or macro-scale information from large volumes of unlabeled data and generate generic features for drugs and proteins. Second, it represents drugs and proteins by fusing cross-scale information through a self-supervised task. Finally, it employs a Transformer Encoder-based model to predict synergy scores, taking representations of drugs in the combinations and the associated proteins of cell lines as input. We compared our method with eight advanced methods across three typical scenarios based on two public datasets. The results consistently demonstrated that the proposed method's generalization ability outperforms six advanced methods'. We also conducted experiments including but not limited to ablation study and case study to further exhibit the effectiveness of MMFSynergy.