Defining cardiotoxic pathways of Tyrosine Kinase Inhibitors- Ethan Schwendeman
Defining cardiotoxic pathways of Tyrosine Kinase Inhibitors
“Renal cell carcinoma (RCC) is the most common form of kidney cancer. Pazopanib, a tyrosine kinase inhibitor (TKI) is the first line therapy for advanced RCC and second line therapy for soft tissue sarcoma. Pazopanib blocks vascular endothelial growth factors (VEGFRs), preventing angiogenesis and delaying cancerous tumor growth and spread. However, pazopanib leads to serious cardiovascular side effects from association with the development of hypertension, QT interval prolongation, a precursor to arrhythmia, heart failure and other cardiovascular events.
Cardiotoxicity causes morbidity and mortality in cancer patients. The cardiotoxic mechanisms of TKIs are still largely unknown. Defining these mechanisms is necessary to better understand the underlying pathologies, help in early intervention, surveillance, and improve clinical outcomes. We hypothesized that pazopanib alters cardiac membrane excitability via sodium channel modifications which would potentially cause arrhythmias.
Methods
21-day dosing trials were performed in cohorts of 6 experimental and 6 control wild-type C57BL/6J mice per cohort. Dosing via oral gavage was performed daily; experimental groups received pazopanib (100mg/kg) in 2.5% DMSO vehicle solution, while control groups were dosed with the vehicle DMSO (2.5%). Once a week, mice were weighed, blood pressure readings were recorded using a CODA system, and surface electrocardiograms and echocardiograms were done using a Vevo2100 echo machine.
Once a trial was completed, organs were extracted and weighed. Heart lysates were used for immunoblotting to test different antibodies of interest. Additionally, ventricular myocyte isolations were performed for immunofluorescence, confocal imaging and electrophysiological studies.
Results
Our results show an increase in mean arterial pressure over time in pazopanib-treated mice. Electrophysiological studies demonstrated irregular membrane excitability such as longer action potential duration, delayed afterdepolarizations and QT interval prolongation. Additionally, patch clamping showed that there is a frequency dependent decrease in inward late sodium current. These findings are in line with our initial hypothesis that pazopanib affects ion channels in cardiomyocytes.
Conclusion
Pazopanib alters cardiomyocyte membrane excitability which could lead to serious fatal arrhythmias. Further studies of more test groups, looking at calcium channels, analyzing other important proteins associated with these ion channels, and studying other similar TKIs will help build a general mechanistic pathway of this class of drugs.”
Very nice work, Ethan. It makes sense that tyrosine kinase inhibitors would affect receptors in other tissues and organs in addition to the desired VEGF receptors. Do you think the cardiotoxic effects are due to inhibition of cardiac tyrosine kinase receptors, or just non-specific effects?