Tyrosine Kinase Inhibitors-Induced Arrhythmias: From Molecular Mechanisms, Pharmacokinetics to Therapeutic Strategies

Abstract

With the development of anti-tumor drugs, tyrosine kinase inhibitors (TKIs) are an indispensable part of targeted therapy. They can be superior to traditional chemotherapeutic drugs in selectivity, safety, and efficacy. However, they have been found to be associated with serious adverse effects in use, such as myocardial infarction, fluid retention, hypertension, and rash. Although TKIs induced arrhythmia with a lower incidence than other cardiovascular diseases, much clinical evidence indicated that adequate attention and management should be provided to patients. This review focuses on QT interval prolongation and atrial fibrillation (AF) which are conveniently monitored in clinical practice. We collected data about TKIs, and analyzed the molecule mechanism, discussed the actual clinical evidence and drug-drug interaction, and provided countermeasures to QT interval prolongation and AF. We also pooled data to show that both QT prolongation and AF are related to their multi-target effects. Furthermore, more than 30 TKIs were approved by the FDA, but most of the novel drugs had a small sample size in the preclinical trial and risk/benefit assessments were not perfect, which led to a suspension after listing, like nilotinib. Similarly, vandetanib exhibits the most significant QT prolongation and ibrutinib exhibits the highest incidence in AF, but does not receive enough attention during treatment.

Cardiotoxicity Induced by Protein Kinase Inhibitors in Patients with Cancer

“…The mechanism of KI-induced cardiotoxicity is not fully understood. Examples of KIs with their cardiotoxic effects and the underlying molecular and cellular pathways are presented in Table 2 [ 29 , 30 , 31 , 32 , 33 ]. Generally, the mechanisms of cardiac toxicity can be divided into on-target and off-target mechanisms [ 33 ].…”

“…Examples of KIs with their cardiotoxic effects and the underlying molecular and cellular pathways are presented in Table 2 [ 29 , 30 , 31 , 32 , 33 ]. Generally, the mechanisms of cardiac toxicity can be divided into on-target and off-target mechanisms [ 33 ]. On-target mechanisms occur when the inhibition of a molecule by KIs causes an anticancer effect in malignant cells but also leads to toxicity in normal cells.…”

“…One of the on-target mechanisms underlying the development of arrhythmia can be PI3K blockage. It leads to a rise of persistent sodium current and a reduction in L-type calcium and potassium current as well as QTc prolongation [ 33 ]. An example of an off-target mechanism leading to arrhythmia is ibrutinib-induced inhibition of Tec protein tyrosine kinase responsible for cardioprotective function by regulating the PI3K-Akt pathway [ 29 , 33 ].…”

“…The risk of atrial flutter and atrial fibrillation associated with zanubrutinib treatment appears to be lower (2% in clinical trials) [ 68 ]. Conduction disturbances, rhythm abnormalities, and variations in the QRS amplitude or QRS axis are quite common ECG findings in patients receiving various KIs [ 33 , 91 , 92 , 94 , 95 , 96 ].…”

Investigating the Effect of Tyrosine Kinase Inhibitors on the Interaction between Human Serum Albumin by Atomic Force Microscopy

“…There have been subsequent developments in TKIs, such as nilotinib, dasatinib, bosutinib, and ponatinib, that reduce the resistance of imatinib and improve the efficiency of treatment [ 11 ]. Like other drugs, the distribution and transport of TKIs in the body are mainly dependent on plasma albumin [ 12 ]. Therefore, studying the effects of TKIs on protein–protein interactions makes it possible to develop novel anti-leukemia drugs through these interactions.…”