Abstract
Cancer is a major public health problem while liver cancer is the main cause of global cancer-related deaths. The previous study demonstrates that the 5-year survival rate for advanced liver cancer is only 30%. Few of the first-line targeted drugs including sorafenib and lenvatinib are available, which often develop resistance. Drug combination therapy is crucial for improving the efficacy of cancer therapy and overcoming resistance. However, traditional methods for discovering drug synergy are costly and time consuming. In this study, we developed a novel predicting model PathSynergy by integrating drug feature data, cell line data, drug-target interactions, and signaling pathways. PathSynergy combined the advantages of graph neural networks and pathway map mapping. Comparing with other baseline models, PathSynergy showed better performance in model classification, accuracy, and precision. Excitingly, six Food and Drug Administration (FDA)-approved drugs including pimecrolimus, topiramate, nandrolone_decanoate, fluticasone propionate, zanubrutinib, and levonorgestrel were predicted and validated to show synergistic effects with sorafenib or lenvatinib against liver cancer for the first time. In general, the PathSynergy model provides a new perspective to discover synergistic combinations of drugs and has broad application potential in the fields of drug discovery and personalized medicine.