Using Stem Cells to Determine Tyrosine Kinase Inhibitor-Induced Cardiotoxicity

An adult stem cell-based cardiotoxicity assay might help researchers assess which investigational cancer drugs will harm patients’ heart tissue, potentially causing treatment-associated arrhythmias or heart failure among cancer survivors.

The study, published in Science Translational Medicine, tested the toxicity of US Food and Drug Administration (FDA)-approved tyrosine kinase inhibitors (TKIs) using cardiomyocytes generated from pluripotent stem cells donated by 13 adults (11 healthy volunteers and 2 volunteers who were undergoing cancer treatment). Cell viability, contractility, electrophysiology, and other parameters were measured before and after TKI exposure.

Using study data, the authors proposed a “cardiac safety index” that was highly predictive of “the known cardiotoxicities of FDA black-boxed TKIs,” the authors reported.

The authors also tested TKI cardiotoxicities in different cell types using stem cell-derived endothelial and cardiac fibroblast cells.

“Using high-throughput screening, we determined that vascular endothelial growth factor receptor 2 (VEGFR2)/platelet-derived growth factor receptor (PDGFR)-inhibiting TKIs caused cardiotoxicity” in all cell types, the researchers reported. “Upregulating cardioprotective signaling with exogenous insulin or IGF1 improved [cardiomyocyte] viability during co-treatment with cardiotoxic VEGFR2/PDGFR-inhibiting TKIs.”

Cardiotoxicity might be alleviated with insulin/IGF signaling, they concluded.

They hope to see the assay used in preclinical drug development to spot agents that could cause cardiotoxicities in patients and in the FDA’s regulatory approval process.

“We think it would be great if you could actual expose patients’ heart, brain, liver, or kidney cells to a drug,” prior to clinical testing, said senior study author Joseph C. Wu, MD, PhD, of the Stanford Cardiovascular Institute and the Institute for Stem Cell Biology and Regenerative Medline, Stanford University School of Medicine, in Stanford, California.

Adult stem cell assays using a larger cohort could be used in “preemptively screening potential chemotherapeutic compounds for cardiotoxicities” in the future, they concluded.

The approach could also be used to help personalize cancer treatment decision-making or to predict adverse events in patients undergoing cancer treatment, the team’s work suggests. The researchers published a separate study last year in Nature Medicine showing that stem cell-derived heart cells from patients diagnosed with breast cancer accurately predicted patients’ doxorubicin cardiotoxicity.