Multiscale profiling of tyrosine kinase inhibitor cardiotoxicity reveals mechanosensitive ion channel PIEZO1 as cardioprotective

The tyrosine kinase inhibitor (TKI) sunitinib is an effective cancer treatment, but exposure can result in hypertension and heart failure. To better understand the mechanisms of cardiotoxicity from TKI treatments, Manhas et al. found that piezo-type mechanosensitive ion channel component 1 (PIEZO1) was involved in endothelial dysfunction after sunitinib treatment in vitro and in vivo. Inducing PIEZO1 with an agonist, Yoda1, or by overexpression in human induced pluripotent stem cell–derived endothelial cells improved markers of sunitinib-induced endothelial dysfunction. In a mouse model of TKI-induced cardiotoxicity, treatment with Yoda1 prevented cardiac pathology and decreased cardiac stress markers. Human cardiac organoids showed that sunitinib was toxic only in the presence of endothelial cells, supporting the cell-specific mechanism. Together, these data support a role for PIEZO1 in TKI-induced cardiotoxicity and present a potential avenue for prevention of the pathology. —Brandon Berry