The development of small molecule tyrosine kinase inhibitors (TKIs) has led to a dramatic increase in life expectancy for patients suffering from cancers such as leukemias, carcinomas, and melanomas. TKIs inhibit the kinase phosphorylation activity of hyperactive receptor tyrosine kinases (RTK), thereby stymying the enhanced cell survival, proliferation, and migration phenotypes that are hallmarks of cancer progression. However, some TKIs are linked to severe vascular side effects such as endothelial toxicity and hypertension. Therefore, methods for accurately assessing TKI-induced vascular toxicity (TKI-VT) must be established. In vitro modeling of vascular toxicity and cardiovascular disease is of interest as human adult vascular endothelial cells are difficult to isolate and propagate long-term in culture, and animal models have often proven non-predictive of the drug response in patients. Patient-specific human induced pluripotent stem cell- derived endothelial cells (iPSC-ECs) represent a novel technology for modeling cardiovascular diseases. Human iPSC-ECs have already been successfully applied to understanding basic mechanisms of pulmonary hypertension and obesity-induced endothelial dysfunction. Human iPSC-ECs have also been used to screen for efficacy and toxicity of various cardiovascular drugs. Indeed, our preliminary data shows endothelial dysfunction in patient-specific iPSC-ECs when treated with TKIs. Here, in our multi-PI resubmission, we hypothesize that human iPSC-ECs represent a novel platform for studying the mechanisms and validity of genomic hits in regulating TKI-VT.
S Vascular toxicity is a major cause of drug withdrawal from the pharmaceutical market. This study will investigate the molecular mechanisms of tyrosine kinase inhibitor-induced vascular toxicity (TKI-VT) by examining how human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) respond to TKI treatment. These patient-specific iPSC-ECs will be derived from individuals who have and have not experienced TKI-VT, in hopes of uncovering underlying mechanisms of genetic susceptibility to TKI treatment and vascular toxicity. Results obtained here will provide mechanistic insights into the pathogenesis of TKI-VT and promote the development of therapeutics to rescue TKI-VT.
|Churko, Jared M; Garg, Priyanka; Treutlein, Barbara et al. (2018) Defining human cardiac transcription factor hierarchies using integrated single-cell heterogeneity analysis. Nat Commun 9:4906|