Multiscale mapping of transcriptomic signatures for cardiotoxic drugs

Targeted inhibition of cancer-selective tyrosine kinases (TKI) has become a successful strategy in the treatment of multiple different cancer types. A sever side effect can be the induction of cardiomyopathy. We analyzed, if we could identify transcriptomic signatures induced by different tyrosine kinase inhibitiors in human IPSC-derived cardiomyocytes from healthy donors that might be associated with a cardiotoxic resonse. To investigate, if the predicted transcriptomic signatures are modified by other cell types of the human heart, we here stimulated two cardiomyocyte cell lines either in isolation or in coculture with human coronary arterial endothelial cells (HCAECs) with the TKIs pazopanib or dabrafenib. Overall design: Human iPSC-derived cardiomyocytes were incubated in isolation or in coculture with human coronary arterial endothelial cells (HCAECs) for 48 hrs. HCAECs were separated from cardiomyocytes by a poros membrane. Thereafter, we stimulated isolated and cocultured cardiomyocytes with pazopanib, dabrafenib or vehicle (DMSO). Cardiomyocytes were separately processed for Bulk RNA-seq. HCAEC which were on glass coverslips were fixed with 4%PFA and stained for Actin and DAPI.