Single-cell RNA sequencing greatly advanced our understanding of intratumoral heterogeneity through identifying tumor subpopulations with distinct biologies. However, translating biological differences into treatment strategies is challenging, as we still lack tools to facilitate efficient drug discovery that tackles heterogeneous tumors. One key component of such approaches tackles accurate prediction of drug response at the single-cell level to offer therapeutic options to specific cell subpopulations. Here, we present a transparent computational framework (nicknamed scIDUC) to predict therapeutic efficacies on an individual-cell basis by integrating single-cell transcriptomic profiles with large, data-rich pan-cancer cell line screening datasets. Our method achieves high accuracy, with predicted sensitivities easily able to separate cells into their true cellular drug resistance status as measured by effect size (Cohen9s D > 1). More importantly, we examine our method9s utility with three distinct prospective tests covering different diseases (rhabdomyosarcoma, pancreatic ductal adenocarcinoma, and castration-resistant prostate cancer), and in each our predicted results are accurate and mirrored biological expectations. In the first two, we identified drugs for cell subpopulations that are resistant to standard-of-care (SOC) therapies due to intrinsic resistance or effects of tumor microenvironments. Our results showed high consistency with experimental findings from the original studies. In the third test, we generated SOC therapy resistant cell lines, used scIDUC to identify efficacious drugs for the resistant line, and validated the predictions with in-vitro experiments. Together, scIDUC quickly translates scRNA-seq data into drug response for individual cells, displaying the potential as a first-line tool for nuanced and heterogeneity-aware drug discovery.
