Distinct Endothelial Cell toxicities of Abl Tyrosine Kinase Inhibitors Lead to Arterial Thrombosis Open Access

• Dasatinib, ponatinib, and nilotinib damage endothelial cells in different ways, all of which can contribute to arterial thrombosis

• Asciminib, the most specific Abl inhibitor, does not cause human coronary endothelial cell damage in vitro nor thrombosis in mouse models

Inhibitors targeting Abl-kinase have dramatically improved survival in Philadelphia chromosome positive leukemias. First generation imatinib has minimal cardiovascular side effects while newer agents dasatinib, ponatinib, and nilotinib are more effective cancer treatments, but carry a high risk of arterial thrombosis. The allosteric Abl-kinase inhibitor asciminib was recently approved without long-term cardiovascular follow up. Previous studies reveal disparate effects of dasatinib, ponatinib, and nilotinib on platelets with consistent evidence of endothelial cell (EC) toxicity. Here we explore pro-thrombotic endothelial toxicity mechanisms by comparing exposure to vehicle versus clinically relevant concentrations of imatinib, dasatinib, ponatinib, nilotinib, and asciminib on primary human coronary artery ECs (HCAECs) and mouse models of endothelial injury and vascular thrombosis. Dasatinib and ponatinib increased adhesion of human platelets to HCAECs, specifically when the ECs, but not when the platelets, were exposed to drugs. Dasatinib, ponatinib and nilotinib impaired HCAEC healing in vitro, whereas only nilotinib impaired healing in vivo and increased von Willebrand factor levels in mice. Dasatinib and ponatinib increased early platelet, but not fibrin, accumulation in the mouse cremaster arteriole laser injury-induced thrombosis model and only ponatinib increased platelet-leukocyte aggregate formation. Asciminib had no toxic effect in any of these assays, similar to imatinib. These studies reveal novel and distinct mechanisms by which EC damage induced by dasatinib, ponatinib, and nilotinib contribute to a pro-thrombogenic EC state. The findings suggest the need for distinct side effect prevention strategies and provide preclinical data supporting vascular safety of asciminib, while awaiting long term vascular safety follow up results.