Kinase inhibitor-induced cardiotoxicity assessed in vitro with human pluripotent stem cell derived cardiomyocytes

Authors: Xian HQ, Blanco C, Bonham K, and Snodgrass HR.

Toxicology and Applied Pharmacology, 2022.

Researchers suggest that combining preclinical cardiotoxicity testing methods may lead to safer cancer treatments and faster, cheaper drug development.

Many small molecule kinase inhibitors (SMKIs) used to treat cancer and other conditions have been associated with serious adverse cardiac events such as left ventricular dysfunction, cardiomyopathy, heart failure, QT prolongation, and Torsades de Pointes, despite the fact that these potential effects were not detected with traditional preclinical drug development testing methods. Because SMKI-associated cardiotoxicities include both electrophysiological and non-electrophysiological effects, the hERG assay analysis currently recommended by the U.S. Food and Drug Administration may fail to identify potential safety issues early on—a failure that can result in late-stage termination of drug development programs, post-approval market withdrawal, and threats to patient health.

In this study, researchers suggest that current cardiotoxicity assessments for SMKIs are insufficient, and instead use a combination of microplate-based fluorescent or luminescent assays and Axion’s Maestro microelectrode array (MEA) platform to explore the effects of multiple SMKIs on human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). The results, which showed high concordance with clinically reported adverse events associated with SMKIs, demonstrated that combined testing detected cardiotoxicities better and revealed mechanistic information related to cardiomyocyte toxicities including apoptosis, mitochondrial membrane depolarization, oxidative stress, and energy depletion. Overall, the authors suggest that combining testing methods can provide a more comprehensive assessment of drug-induced cardiotoxicity early in development, which could improve patient safety and save time and money for drug developers.