Mechanisms, monitoring, and management of tyrosine kinase inhibitors-associated cardiovascular toxicities

Abstract

The tyrosine kinase inhibitor (TKI) drug class is a prominently used option in the treatment of various cancers. Safety evaluation of these drugs has shown evidence of cardiotoxicity of varying frequency and severity between agents; concern has led to updated labeling, warning prescribers of such. This review seeks to clarify the present dangers and investigate cardiotoxic mechanisms of action for each discussed TKI. Dasatinib was connected primarily with an incidence of fluid retention, edema, QT prolongation, and pulmonary hypertension in clinical studies. It is theorized that this is due to a combination of off-target kinase binding and on-target binding of Bcr-Abl, and less likely, mitochondrial induced apoptosis. Studies showed sorafenib to carry the risk of hypertension, QT prolongation, and myocardial infarction. Proposed mechanisms for these side effects include inhibition of proteins, vascular endothelium growth factor receptor, hERG potassium channels, and the RAF/MERK/ERK pro-survival pathway. Finally, lapatinib showed evidence of decreased left ventricular ejection fraction (LVEF) and QT prolongation in clinical studies. The literature attributes these as side effects of on-target ErbB2 binding leading to mitochondrial induced apoptosis. The concern warranted by these findings is in question. Pooled safety data suggest that the overall risk for cardiotoxicity is minimal in dasatinib and lapatinib. Sorafenib seems to carry a moderate concern. For the discussed agents, recommendations agree that routine monitoring via methods such as electroencephalogram, cardiac biomarkers, and blood pressure is warranted during the course of treatment, in addition to a comprehensive collection of past medical history and risk factors to identify those at heightened risk for cardiovascular events.

Towards grouping concepts based on new approach methodologies in chemical hazard assessment: the read-across approach of the EU-ToxRisk project

“…(ii) Cardiotoxicity can be caused by the inhibition of the hERG channel, a potassium channel of high importance for the synchronisation of cardiomyocyte contraction across the whole organ. It has been shown that several drug classes, such as various neuroleptics or also modern tyrosine kinase inhibitors (TKIs) inhibit hERG and cause arrhythmias (Chaar et al 2018). Again, the mechanistic events measurable by NAM have good predictivity for organ-or organism-level adverse outcomes.…”

Risk of QTc prolongation among cancer patients treated with tyrosine kinase inhibitors

“…8 Subsequently, vascular toxicities were also recognized as well as arrhythmias including QTc prolongation. 8,[9][10][11][12] The latter are reportedly far more common with TKIs than with classical chemotherapeutics, but incidences in real-world clinical practice remain to be defined for many TKIs. This topic does deserve particular attention as QTc prolongation can lead to lethal arrhythmias including ventricular tachycardia and fibrillation, especially Torsades de Pointes (TdP), and sudden cardiac death (SCD).…”

Exploring receptor tyrosine kinases-inhibitors in Cancer treatments

“…Notwithstanding, the success of type I kinase inhibitors, come the associated cardiotoxicity and cardiac failures due to off-target binding [66]. In this regard, there should be routine observation during the treatment with type I kinase inhibitors, in addition to an all-inclusive assessment of medical history and predisposing factor to identify patients that are predisposed to cardiovascular issues [67].…”