Using DeepSignalingFlow to mine signaling flows interpreting mechanism of synergy of cocktails

Heming Zhang; Yixin Chen; Philip Payne; Fuhai Li

Using DeepSignalingFlow to mine signaling flows interpreting mechanism of synergy of cocktails

2024

Heming Zhang | Yixin Chen | Philip Payne | Fuhai Li

Abstract Complex signaling pathways are believed to be responsible for drug resistance. Drug combinations perturbing multiple signaling targets have the potential to reduce drug resistance. The large-scale multi-omic datasets and experimental drug combination synergistic score data are valuable resources to study mechanisms of synergy (MoS) to guide the development of precision drug combinations. However, signaling patterns of MoS are complex and remain unclear, and thus it is challenging to identify synergistic drug combinations in clinical. Herein, we proposed a novel integrative and interpretable graph AI model, DeepSignalingFlow, to uncover the MoS by integrating and mining multi-omic data. The major innovation is that we uncover MoS by modeling the signaling flow from multi-omic features of essential disease proteins to the drug targets, which has not been introduced by the existing models. The model performance was assessed utilizing four distinct drug combination synergy evaluation datasets, i.e., NCI ALMANAC, O’Neil, DrugComb, and DrugCombDB. The comparison results showed that the proposed model outperformed existing graph AI models in terms of synergy score prediction, and can interpret MoS using the core signaling flows. The code is publicly accessible via Github: https://github.com/FuhaiLiAiLab/DeepSignalingFlow

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