Cardiotoxicity of small-molecule kinase inhibitors in cancer therapy

Figures

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  Fig. 1. Timeline for the FDA and NMPA approval of small-molecule kinase inhibitors. The figure shows the small-molecule kinase inhibitors approved by the FDA and NMPA from 2001 to 2023. Except for the red star representing small-molecule inhibitors approved by NMPA, all others are FDA-approved. The green box shows tyrosine kinase inhibitors, while the pink box shows ser/thr kinase inhibitors, and the black box shows drugs with black box warnings. Green represents the incidence of cardiotoxicity events induced by small molecule inhibitors

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  Fig. 2. Cardiovascular toxicities of small-molecule kinase inhibitors. The figure shows the cardiotoxicity events induced by small molecule inhibitors, including myocarditis, atrial fibrillation, hypertension, QT interval prolongation, LV dysfunction, pericardial effusion, heart failure, and myocardial infarction or ischemia. We have identified small molecule inhibitors that induce corresponding cardiotoxicity

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  Fig. 3. Mechanisms of SMKIs-induced cardiotoxicity. Osimertinib exhibits simultaneous inhibition of the hERG potassium channel, Nav1.5 sodium channel, and L-type Ca2+ channel, all of which are involved in myocardial cell conduction. This inhibition leads to the prolongation of both the PR interval and QT interval. Afatinib specifically targets the EGFR and HER2 receptors, resulting in the blockade of the PI3K/AKT pathway. This blockade subsequently leads to the accumulation of ROS and the initiation of cell apoptosis, resulting in mitochondrial damage, ultimately inducing heart failure. Moreover, lapatinib also induces oxidative stress in myocardial cells through the PI3K/AKT pathway, further contributing to cardiotoxicity. Lastly, TKIs such as sorafenib or sunitinib selectively target the VEGFR and PDGFR receptors. Hypertension is a prevalent cardiotoxicity associated with VEGFR inhibitors, primarily attributed to the inhibition of downstream signaling pathways, such as ERK/AKT, after VEGF inhibition. This inhibition results in a reduction in the production of NOS and NO by endothelial cells, leading to vasoconstriction and the eventual development of hypertension. Furthermore, elevated…