scGSDR: Harnessing Gene Semantics for Single-Cell Pharmacological Profiling

The rise of single-cell sequencing technologies has revolutionized the exploration of drug resistance, revealing the crucial role of cellular heterogeneity in advancing precision medicine. By building computational models from existing single-cell drug response data, we can rapidly annotate cellular responses to drugs in subsequent trials. To this end, we developed scGSDR, a model that integrates two computational pipelines grounded in the knowledge of cellular states and gene signaling pathways, both essential for understanding biological gene semantics. scGSDR enhances predictive performance by incorporating gene semantics and employs an interpretability module to identify key pathways contributing to drug resistance phenotypes. Our extensive validation, which included 16 experiments covering 11 drugs, demonstrates scGSDR's superior predictive accuracy, when trained with either bulk-seq or scRNA-seq data, achieving high AUROC, AUPR, and F1 Scores. The model's application has extended from single-drug predictions to scenarios involving drug combinations. Leveraging pathways of known drug target genes, we found that scGSDR's cell-pathway attention scores are biologically interpretable, which helped us identify other potential drug-related genes. Literature review of top-ranking genes in our predictions such as BCL2, CCND1, the AKT family, and PIK3CA for PLX4720; and ICAM1, VCAM1, NFKB1, NFKBIA, and RAC1 for Paclitaxel confirmed their relevance. In conclusion, scGSDR, by incorporating gene semantics, enhances predictive modeling of cellular responses to diverse drugs, proving invaluable for scenarios involving both single drug and combination therapies and effectively identifying key resistance-related pathways, thus advancing precision medicine and targeted therapy development.