Cardiotoxicity Evaluation of Tyrosine Kinase Inhibitors using Human Induced Pluripotent Stem Cell-derived Healthy and Long QT Syndrome Cardiomyocytes

Abstract

Background Cardiotoxicity associated with tyrosine kinase inhibitors (TKIs) has been reported in several clinical trials and preclinical studies, whereas the toxicity in populations with congenital electrophysiological dysfunction remains unclarified. Methods We studied cardiotoxicities of four US Food and Drug Administration (FDA)-approved TKIs with different targets by measuring changes in cardiomyocyte (CM) contractility. Contractions of human induced pluripotent stem cell-derived (hiPSC)-CMs from healthy donors and long QT syndrome (LQT) patients were studied with an impedance-based bioanalytical method (xCELLigence® real-time cell analysis [RTCA] cardio system) to quantify TKI toxicity. Results Both healthy donor (wild type, WT)- and LQT patient-derived hiPSC-CMs exhibited a functional CM phenotype. The four TKIs inhibited the growth and contractility of CMs with different potencies. Crizotinib and dasatinib decreased the beating of both WT- and LQT-hiPSC-CMs with approximately equal potencies. Sunitinib weakened spontaneous pulsations of both kinds of cells, but the LQT-hiPSC-CMs showed higher sensitivity. In contrast, lapatinib exerted a milder effect on LQT- hiPSC-CMs. Conclusions Crizotinib, sunitinib, and lapatinib have a higher risk of inducing adverse cardiac events than dasatinib, and LQT1 patients should be particularly cautious with sunitinib. HiPSC-CMs derived from both healthy and patient-specific donors could improve precision medicine and preclinical cardiotoxicity evaluations.