Cell Village Captures Populational Heterogeneity of Sunitinib Cardiotoxicity

BACKGROUND: TKIs (tyrosine kinase inhibitors) have transformed cancer therapy; however, cardiotoxicity remains a frequent adverse effect with variable susceptibility among patients. For sunitinib, a commonly prescribed TKI, the molecular programs and functional features underlying this variability are not well defined, and clinically actionable predictors of cardiotoxicity risk remain lacking. METHODS: To investigate interindividual variability in sunitinib-induced cardiotoxic responses, we implemented the Cell Village platform consisting of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes from 20 healthy donors. Pooled iPSCs were differentiated into cardiomyocytes, treated with sunitinib for 72 hours, followed by harvesting for single-nucleus RNA sequencing. Donor identity was determined using single nucleotide polymorphism-based demultiplexing. Additionally, individual line-specific transcriptomic responses to sunitinib were integrated with quantitative functional phenotyping (including contractility, electrophysiology, and recovery efficacy following tocotrienol treatment) in iPSC-derived cardiomyocytes differentiated from a subset of 10 lines. RESULTS: Sunitinib induced a robust global transcriptional response characterized by dysregulation of tyrosine kinase signaling, cytoskeletal organization, ion channels, and calcium-handling pathways. Although the pathway-level changes were shared, individual donor lines displayed heterogeneity in both gene expression patterns and functional impairment. Across functional parameters, relaxation velocity was the most consistently correlated with toxicity severity. Integration of each iPSC line's functional data with the corresponding transcriptomic signatures identified gene modules related to calcium handling and structural organization strongly correlated with donor-specific toxicity and recovery indices. Pharmacological validation using tocotrienol demonstrated partial, donor-dependent improvement of sunitinib-related iPSC-derived cardiomyocyte impairments. CONCLUSIONS: This proof-of-concept study establishes a scalable, donor-resolved platform that links pooled transcriptomic profiling with functional toxicity and recovery phenotypes in human cardiomyocytes. By linking molecular perturbations to functional outcomes across genetically diverse backgrounds, this approach provides a framework for dissecting interindividual variability in TKI-associated cardiotoxicity. More broadly, it provides a foundation for extending population-scale cardiotoxicity assessment to additional drugs and protective interventions.