Abstract
Cancer drug combination therapies offer a promising strategy to overcome resistance and improve treatment efficacy, but identifying synergistic drug pairs is challenging due to complex biological interactions and tumor heterogeneity. Current machine learning algorithms for drug synergy prediction primarily rely on large-scale, multimodal datasets, yet suffer from critical limitations including poor interpretability, difficulty distinguishing causative biological relationships from correlations, and inadequate modeling of cancer-specific molecular interactions. To address these challenges, we propose CASynergy (Causal Attention and Cross-attention Synergy), a novel deep learning model for predicting cancer drug synergy that addresses limitations of prior approaches in accuracy and interpretability. CASynergy introduces a causal attention mechanism to distinguish true causal genomic features from spurious correlations, cell line-specific gene network construction to capture the unique molecular context of each cancer cell line, and a cross-attention module to integrate drug molecular features with cell line gene expression profiles. These improvements allow CASynergy to clearly identify significant drug-gene interactions and provides interpretable insights into why a combination is predicted to be synergistic. Experiments on two benchmark datasets (DrugCombDB and Oncology-Screen) suggests that CASynergy outperformed five state-of-the-art models. CASynergy offers a better and more reliable way to predict effective drug combinations. It works well across different cancer types and is easier to understand, which is important for personalized cancer treatment and finding new drugs.