Abstract 110: Pro-thrombotic BCR-ABL Tyrosine Kinase Inhibitors Ponatinib And Nilotinib, But Not The Novel Agent Asciminb, Impair Endothelial Cell Wound Healing

Abstract

Introduction: Tyrosine kinase inhibitors (TKIs) targeting ABL kinase have transformed the treatment of BCR-ABL positive leukemias. First generation imatinib is well tolerated while the newer TKIs, ponatinib and nilotinib, are more effective for leukemia but both substantially increase risk of acute arterial thrombosis, thereby limiting their clinical benefit over imatinib. Asciminib is a new BCR-ABL inhibitor with an unknown safety profile. We previously showed that BCR-ABL inhibitors that increase thrombosis in humans also cause toxicity in endothelial cells (ECs). Hypothesis: We hypothesize that BCR-ABL TKIs that cause EC dysfunction in vitro delay healing at sites of vascular injury in vivo as a potential mechanism of increased risk of thrombosis. Methods: We used the in vitro scratch wound assay and western blot for endothelial nitric oxide synthase (eNOS) phosphorylation in human umbilical vein (HUV)ECs and a mouse carotid artery wire injury model to assess the impact of BCR-ABL TKIs on EC wound healing capacity in vitro and in vivo . Results: ECs were treated with the Cmax concentration in cancer patients, as were mice, as confirmed by serum LC-MS. In vitro , ponatinib and nilotinib significantly decreased HUVEC wound healing compared to both imatinib and asciminib (p<0.001), with no difference between imatinib and asciminib. Ponatinib significantly decreased peNOS compared to both imatinib and nilotinib (<0.05), while asciminib was not significantly different from any of the other TKIs. In vivo , nilotinib significantly decreased carotid EC wound healing compared to imatinib and asciminib (p< 0.05), while ponatinib was not significantly different from any other TKIs. Carotid thrombosis after wire injury was observed in 3/26 mice treated with ponatinib, 5/23 with nilotinib, 1/21 with asciminib, and 0/26 treated with imatinib, with clot-free survival studies ongoing. Conclusions: Ponatinib and nilotinib cause EC toxicity by distinct mechanisms in vitro , which has implications for mitigating their cardiovascular risk. Asciminib causes little vascular toxicity in vitro or in vivo by these assays. Carotid thrombosis developed in some TKI treated mice, suggesting this model can be used to study the link between impaired EC healing and thrombosis.