biostudies-literatureHansen JU.S. Department of Health & Human Services | U.S. Food and Drug AdministrationU.S. Department of Health & Human Services | U.S. Food and Drug Administration (U.S. Food & Drug Administration)NHGRI NIH HHSNCI NIH HHSU.S. Department of Health & Human Services | National Institutes of Health (NIH)U.S. Department of Health & Human Services | National Institutes of Health7968https://www.ebi.ac.uk/biostudies/studies/S-EPMC11390749biostudies-literatureUnknown15(1)Drug-induced gene expression profiles can identify potential mechanisms of toxicity. We focus on obtaining signatures for cardiotoxicity of FDA-approved tyrosine kinase inhibitors (TKIs) in human induced-pluripotent-stem-cell-derived cardiomyocytes, using bulk transcriptomic profiles. We use singular value decomposition to identify drug-selective patterns across cell lines obtained from multiple healthy human subjects. Cellular pathways affected by cardiotoxic TKIs include energy metabolism, contractile, and extracellular matrix dynamics. Projecting these pathways to published single cell expression profiles indicates that TKI responses can be evoked in both cardiomyocytes and fibroblasts. Integration of transcriptomic outlier analysis with whole genomic sequencing of our six cell lines enNature communicationsMultiscale mapping of transcriptomic signatures for cardiotoxic drugs.PMC113907495U54HG00809875F40119C10021P30 CA008748U54 HG008098Azeloglu EUGoldfarb JSchaniel CMartinez PSebra RDubois NCXiong YYadaw ASBerger SIChen YIyengar RBeaumont KGJayaraman GChan ASchurer SCShewale BHu BGallo JMTolentino REDhanan PVidovic DSiddiq MMHansen JSobie EABirtwistle MRfalseMultiscale mapping of transcriptomic signatures for cardiotoxic drugs.Drug-induced gene expression profiles can identify potential mechanisms of toxicity. We focus on obtaining signatures for cardiotoxicity of FDA-approved tyrosine kinase inhibitors (TKIs) in human induced-pluripotent-stem-cell-derived cardiomyocytes, using bulk transcriptomic profiles. We use singular value decomposition to identify drug-selective patterns across cell lines obtained from multiple healthy human subjects. Cellular pathways affected by cardiotoxic TKIs include energy metabolism, contractile, and extracellular matrix dynamics. Projecting these pathways to published single cell expression profiles indicates that TKI responses can be evoked in both cardiomyocytes and fibroblasts. Integration of transcriptomic outlier analysis with whole genomic sequencing of our six cell lines en2024-01-01T00:00:00Z2024 Sep2026-06-02T04:51:57.961Z2025-04-04T11:04:02.792ZS-EPMC113907493926148110.1038/s41467-024-52145-4