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. Graphical Abstract