The concept of synthetic lethality(SL)has been successfully used for targeted therapies.To further explore SL for cancer therapy,identifying more SL interactions with therapeutic potential are essential.Recently,graph...The concept of synthetic lethality(SL)has been successfully used for targeted therapies.To further explore SL for cancer therapy,identifying more SL interactions with therapeutic potential are essential.Recently,graph neural network-based deep learning methods have been proposed for SL prediction,which reduce the SL search space of wet-lab based methods.However,these methods ignore that most SL interactions depend strongly on genetic context,which limits the application of the predicted results.In this study,we proposed a graph recurrent network-based model for specific context-dependent SL prediction(SLGRN).In particular,we introduced a Graph Recurrent Network-based encoder to acquire a context-specific,low-dimensional feature representation for each node,facilitating the prediction of novel SL.SLGRN leveraged gate recurrent unit(GRU)and it incorporated a context-dependent-level state to effectively integrate information from all nodes.As a result,SLGRN outperforms the state-of-the-arts models for SL prediction.We subsequently validate novel SL interactions under different contexts based on combination therapy or patient survival analysis.Through in vitro experiments and retrospective clinical analysis,we emphasize the potential clinical significance of this context-specific SL prediction model.展开更多
基金supported by the National Key Research and Development Program of China(2023YFC2604400)the National Natural Science Foundation of China(62103436)。
文摘The concept of synthetic lethality(SL)has been successfully used for targeted therapies.To further explore SL for cancer therapy,identifying more SL interactions with therapeutic potential are essential.Recently,graph neural network-based deep learning methods have been proposed for SL prediction,which reduce the SL search space of wet-lab based methods.However,these methods ignore that most SL interactions depend strongly on genetic context,which limits the application of the predicted results.In this study,we proposed a graph recurrent network-based model for specific context-dependent SL prediction(SLGRN).In particular,we introduced a Graph Recurrent Network-based encoder to acquire a context-specific,low-dimensional feature representation for each node,facilitating the prediction of novel SL.SLGRN leveraged gate recurrent unit(GRU)and it incorporated a context-dependent-level state to effectively integrate information from all nodes.As a result,SLGRN outperforms the state-of-the-arts models for SL prediction.We subsequently validate novel SL interactions under different contexts based on combination therapy or patient survival analysis.Through in vitro experiments and retrospective clinical analysis,we emphasize the potential clinical significance of this context-specific SL prediction model.
