Adaptation of Human iPSC-Derived Cardiomyocytes to Tyrosine Kinase Inhibitors Reduces Acute Cardiotoxicity via Metabolic Reprogramming.

ABSTRACT: Tyrosine kinase inhibitors (TKIs) are widely used to treat solid tumors but can be cardiotoxic. The molecular basis for this toxicity and its relationship to therapeutic mechanisms remain unclear; we therefore undertook a systems-level analysis of human cardiomyocytes (CMs) exposed to four TKIs. CMs differentiated from human induced pluripotent stem cells (hiPSCs) were exposed to sunitinib, sorafenib, lapatinib, or erlotinib, and responses were assessed by functional assays, microscopy, RNA sequencing, and mass spectrometry (GEO: GSE114686; PRIDE: PXD012043). TKIs have diverse effects on hiPSC-CMs distinct from inhibition of tyrosine-kinase-mediated signal transduction; cardiac metabolism is particularly sensitive. Following sorafenib treatment, oxidative phosphorylation is downregulated,

SUBMITTER: Wang H 

PROVIDER: S-EPMC6657491 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature