Abstract 234: Physiological Toxicity Assessment of Tyrosine Kinase Inhibitors with Human Induced Pluripotent Stem Cell Cardiomyocytes

Abstract

Tyrosine kinase inhibitors (TKIs) have improved targeted therapeutics for cancer management despite possible cardiac side effects, including decreased contractility. A combination microelectrode and impedance platform was used to assess field potential (FP) electrical activity and contractility, respectively, after acute and chronic exposure of six TKIs on human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). Four non-TKI drugs were tested to confirm assay sensitivity. hERG current inhibitors dofetilide and pentamidine increased beat rate (BR) corrected FP duration (FPDc). Dofetilide (6μM) induced transient early afterdepolarizations (EADs), characterized as ectopic beats/notching in the FP signal, and decreased impedance amplitude (BAmp) at 48hrs. Multi-channel blocker amiodarone (2μM) acutely decreased FPDc, with quiescence up to 1hr, and increased BAmp after 24hrs. Doxorubicin decreased BAmp, inducing quiescence starting at 48hrs (5μM and 10μM). Nilotinib, sorafenib and sunitinib, which have varying documented risks of clinical QT prolongation and/or cardiotoxicity, increased FPDc. With highest tested doses, nilotinib (6μM) generated persistent EADs and increased BR, sunitinib (2.5μM) produced tachyarrhythmias with minimal impedance-evident contractions that recovered by 24hrs, and sorafenib (10μM) induced quiescence that recovered by 3hrs. Imatinib, erlotinib and lapatinib, which have fewer clinical cardtiotoxic effects, did not cause rhythm disturbances. Erlotinib and lapatinib had no significant effect on FPDc, lapatinib (2.5μM and 5μM) decreased BR, while imatinib (15μM) acutely increased FPDc and increased BR after 48hrs. Tandem electrical and impedance screening in hiPSC-CMs for drug cardiotoxicity was consistent with the clinical experience for TKIs, suggesting its potential utility for preclinical cardiotoxicity assessment for proarrhythmia and decreased contractility.