Drug adaptation influences cardiotoxicity caused by tyrosine kinase inhibitors in iPSC-derived human cardiomyocytes

Abstract

Cardiotoxicity induced by anti-cancer drugs is of increasing concern as the durability of therapeutic responses increases. The molecular basis of cardiotoxicity remains poorly understood, particularly when due to drug classes that do not inhibit the hERG potassium channel or cause the arrhythmias associated with long QT syndrome. This paper describes systematic molecular profiling of one such class of drugs, tyrosine kinase inhibitors (TKIs), which are widely used to treat solid tumors. Human cardiomyocytes differentiated from induced pluripotent stem cells (hiPSC-CMs) were exposed to one of four TKIs (Sunitinib, Sorafenib, Lapatinib and Erlotinib) observed to cause different levels of human cardiotoxicity and profiled by RNA sequencing (RNA-Seq) and mass spectroscopy-based proteomic analysis. We find that TKIs have diverse effects on hiPSC-CMs but genes involved in cardiac metabolism are particularly sensitive. In the case of Sorafenib, many genes involved in oxidative phosphorylation are down regulated resulting in a profound defect in mitochondrial metabolism. Cells adapt to this by upregulating aerobic glycolysis. Metabolic remodeling makes cells less acutely sensitive to Sorafenib and the effect is reversible upon drug withdrawal. Thus, the response of cardiomyocytes to Sorafenib is characterized by adaptive drug resistance previously described in tumor cells.