Insights and perspectives into the etiology of TKI-induced cardiotoxicity

Tyrosine kinase inhibitors (TKIs) are a class of drugs that have significantly improved survival outcomes and revolutionized the treatment landscape for cancer patients. This is due to their ability to suppress the dysregulation of phosphorylation targets contributing to tumor progression; however, many TKIs approved to treat cancer are associated with adverse cardiac events, including potentially lethal cardiotoxicity. Despite extensive research on kinase signaling pathways, the mechanisms that regulate the movement of TKIs across cardiac cell membranes to interfere with the targets associated with TKI-induced cardiotoxicity remain to be fully elucidated. In this review, we focus on (1) summarizing the purported intracellular signaling pathways associated with TKI-induced cardiotoxicity, (2) the interaction of TKIs with membrane transporters, and (3) recent technological and methodological advances that can be leveraged to study the role of membrane transporters in the etiology of TKI-induced cardiotoxicity. Significance Statement: Tyrosine kinase inhibitors (TKIs) have transformed cancer treatment but are increasingly recognized for causing cardiotoxicity. Defining the interplay between TKIs and membrane transporters will improve our mechanistic understanding of cardiotoxicity, particularly how intracellular drug disposition may critically influence susceptibility to essential cardiac kinase targets. Improving our understanding of this mechanism will aid in refining cardiac safety assessments of TKIs and enable transporter-informed strategies to mitigate cardiac risk while maintaining anticancer efficacy.