ProphDR: An Interpretable Deep Learning Model for Predicting Cancer Drug Response via Multi-Omics and Cross-Attention...

Predicting cancer drug responses (CDRs) accurately remains a significant challenge due to the complexity of tumor biology and the limitations of existing "black-box" machine learning models. To address this, we propose ProphDR, an interpretable deep learning framework that integrates multiomics data and drug structural information using a hierarchical attention mechanism. ProphDR incorporates a Criss-Cross Gene-level Multiomics Integration (CGMI) module to capture gene-level features and a cross-attention (CA) module to model drug-gene interactions. Evaluated on datasets from GDSC and CCLE, ProphDR achieves state-of-the-art performance in predicting ln(IC₅₀) values (PCC = 0.938, RMSE = 0.978) and classifying drug sensitivity (AUC = 0.981). It also demonstrates strong generalizability in cold-start scenarios involving unseen drugs or cell lines. Crucially, ProphDR generates biologically interpretable attention maps that highlight key pharmacophores and resistance-related genes such as ERBB2 (HER2), consistent with established mechanisms in NSCLC and BRCA. These insights bridge genomic features with phenotypic outcomes, offering valuable guidance for target prioritization and drug repurposing. ProphDR represents a robust and explainable AI tool for advancing precision oncology.