BACKGROUND: Drug combination therapy often outperforms monotherapy in cancer treatment, but the vast number of available drugs makes manual screening for synergistic combinations costly. Computational methods, especially deep learning, can reduce the search space by predicting likely synergistic drug combinations. Recent studies have improved drug synergy prediction by modeling associations among different biological entities, but drug-drug interactions have not been fully leveraged in this scenario, which motivated the work presented in this paper. METHODS: This paper proposes a deep learning method named HGTSynergy to predict synergistic drug combinations, which employs a heterogeneous graph attention network and a tailored task to capture complex latent patterns in the drug network as prior knowledge. The learned knowledge is then transferred through a transfer learning framework to the downstream task of predicting drug synergy scores, effectively enhancing predictive performance. RESULTS: A five-fold nested cross-validation is employed to train HGTSynergy. In the synergy regression task, HGTSynergy outperforms seven deep learning methods, achieving a mean squared error of 222.83, root mean squared error of 14.91, and Pearson correlation coefficient of 0.75. For the synergy classification task, it also surpasses other methods with an area under the receiver operating characteristic curve of 0.90, area under the precision-recall curve of 0.63, accuracy of 0.94, precision of 0.72, and Cohen's Kappa of 0.52. The ablation study verifies that the heterogeneous graph attention network and the transfer learning framework both have a positive effect on prediction performance. Moreover, a series of analyses demonstrates that the proposed method exhibits strong generalization performance and interpretability. The case study further validates its consistency with prior research. CONCLUSIONS: This study suggests that drug synergy prediction can be improved by comprehensively modeling diverse drug-drug interaction types and leveraging transfer learning to extract prior knowledge from them. The ability of HGTSynergy to discover new anticancer synergistic drug combinations outperforms other state-of-the-art methods. HGTSynergy promises to be a powerful tool to pre-screen 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.

Synthetic lethality (SL) refers to the phenomenon that simultaneous mutation of two genes is lethal to cells, while mutation of either gene alone is not lethal. Exploiting this genetic interaction holds immense clinical potential for selectively killing cancer cells without harming normal cells. Given the vast genomic combinatorial space, relying solely on wet lab experiments for screening synthetic lethal gene pairs is impractical, leading to the emergence of various computational methods. Existing computational methods often rely on single-feature extraction methods or single data sources for prediction, resulting in poor predictive accuracy when faced with unseen genes. In this work, we propose a novel deep ensemble model for synthetic lethality prediction based on a stacking strategy (DSESL). Firstly, leveraging the publicly available SynLethKG knowledge graph, we learn gene embed dings at three different focus-levels: single-entity single-relation, single-entity multi-relation, and multi-entity multi-relation, constructing three sub-models for prediction from the knowledge graph. Additionally, we incorporate signaling pathway data and utilize graph neural network-based methods to construct a pathway sub-model. Finally, we adopt a stacking strategy-based ensemble approach to effectively integrate the prediction results from different sub-models. Based experimental results, our proposed DSESL model outperforms existing state-of-the-art SL prediction methods in all three prediction scenarios. The source code of DSESL is available at https://github.com/TOJSSE-iData/DSESL/.

BACKGROUND: The discovery of anticancer drug combinations is a crucial work of anticancer treatment. In recent years, pre-screening drug combinations with synergistic effects in a large-scale search space adopting computational methods, especially deep learning methods, is increasingly popular with researchers. Although achievements have been made to predict anticancer synergistic drug combinations based on deep learning, the application of multi-task learning in this field is relatively rare. The successful practice of multi-task learning in various fields shows that it can effectively learn multiple tasks jointly and improve the performance of all the tasks. METHODS: In this paper, we propose MTLSynergy which is based on multi-task learning and deep neural networks to predict synergistic anticancer drug combinations. It simultaneously learns two crucial prediction tasks in anticancer treatment, which are synergy prediction of drug combinations and sensitivity prediction of monotherapy. And MTLSynergy integrates the classification and regression of prediction tasks into the same model. Moreover, autoencoders are employed to reduce the dimensions of input features. RESULTS: Compared with the previous methods listed in this paper, MTLSynergy achieves the lowest mean square error of 216.47 and the highest Pearson correlation coefficient of 0.76 on the drug synergy prediction task. On the corresponding classification task, the area under the receiver operator characteristics curve and the area under the precision-recall curve are 0.90 and 0.62, respectively, which are equivalent to the comparison methods. Through the ablation study, we verify that multi-task learning and autoencoder both have a positive effect on prediction performance. In addition, the prediction results of MTLSynergy in many cases are also consistent with previous studies. CONCLUSION: Our study suggests that multi-task learning is significantly beneficial for both drug synergy prediction and monotherapy sensitivity prediction when combining these two tasks into one model. The ability of MTLSynergy to discover new anticancer synergistic drug combinations noteworthily outperforms other state-of-the-art methods. MTLSynergy promises to be a powerful tool to pre-screen anticancer synergistic drug combinations.

Although drug combinations in cancer treatment appear to be a promising therapeutic strategy with respect to monotherapy, it is arduous to discover new synergistic drug combinations due to the combinatorial explosion. Deep learning technology holds immense promise for better prediction of in vitro synergistic drug combinations for certain cell lines. In methods applying such technology, omics data are widely adopted to construct cell line features. However, biological network data are rarely considered yet, which is worthy of in-depth study. In this study, we propose a novel deep learning method, termed PRODeepSyn, for predicting anticancer synergistic drug combinations. By leveraging the Graph Convolutional Network, PRODeepSyn integrates the protein-protein interaction (PPI) network with omics data to construct low-dimensional dense embeddings for cell lines. PRODeepSyn then builds a deep neural network with the Batch Normalization mechanism to predict synergy scores using the cell line embeddings and drug features. PRODeepSyn achieves the lowest root mean square error of 15.08 and the highest Pearson correlation coefficient of 0.75, outperforming two deep learning methods and four machine learning methods. On the classification task, PRODeepSyn achieves an area under the receiver operator characteristics curve of 0.90, an area under the precision-recall curve of 0.63 and a Cohen's Kappa of 0.53. In the ablation study, we find that using the multi-omics data and the integrated PPI network's information both can improve the prediction results. Additionally, the case study demonstrates the consistency between PRODeepSyn and previous studies.