Endothelium as a mediator of BCR-ABL tyrosine kinase inhibitor vascular toxicity

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Tyrosine kinase inhibitors (TKIs) that target BCR-ABL have transformed Chronic Myelogenous Leukemia (CML) from a deadly condition with a poor prognosis to a manageable chronic disease with a life expectancy close to that of the normal population, resulting in an increase in the prevalence of CML that is expected to continue to rise until at least 2050. This success is driven by newer generations of BCR-ABL TKIs with improved potency. Some BCR-ABL TKIs however, most notably dasatinib, ponatinib and nilotinib, have been associated with cardiovascular toxicity including increased risk of arterial thrombotic events such as coronary artery thrombosis, peripheral arterial occlusion, and cerebrovascular accidents. Our lab previously helped develop a proteomic approach which identified a phospho-proteomic signature of human umbilical vein endothelial cells (HUVECs) treated with BCR-ABL TKIs that predicts clinical vascular toxicity and correlates with endothelial cell (EC) dysfunction in vitro. ECs line the vessel lumen and protect the vasculature from pathologic platelet adhesion and thrombosis. Conversely, EC dysfunction that impairs the ability of ECs to heal also exposes prothrombotic factors on the basement membrane that, along with EC upregulation of pro-coagulant proteins, are unexplored mechanisms by which BCR-ABL TKI toxicity could contribute to increased risk of arterial thrombosis. Asciminib, a novel allosteric BCR-ABL inhibitor, has expanded the landscape of treatment in CML and in 2021 received FDA approval for patients who have failed two prior BCR-ABL TKIs. The cardiovascular safety profile of asciminib and its effects on ECs in vitro is unknown, nor are mitigating strategies available for BCR-ABL TKI vascular toxicity. New preliminary data from our lab support that asciminib is less toxic than ponatinib, dasatinib, and nilotinib in a HUVEC scratch would healing assay in vitro, that ponatinib impairs mouse carotid artery endothelial cell wound healing in vivo, and that phospho-proteomic screening can identify drugs that “reverse” the toxic BCR- ABL TKI phospho-proteomic signature and improve EC survival after BCR-ABL TKI exposure. We propose to use in vitro assays to compare the EC toxicity of asciminib to imatinib (non-toxic BCR-ABL TKI), ponatinib, nilotinib, and dasatinib (all known to be toxic to ECs), and explore the EC toxicity of these compounds in vivo in a mouse carotid artery wire injury model. We also propose to use proteomics to determine the phospho- proteomic profile of HUVECs treated with asciminib, screen approved cardiometabolic drugs for their ability to “reverse” the phospho-proteomic EC signature of toxic BCR-ABL TKIs, and test whether the target drugs identified by our screen can reverse EC toxicity in vitro and in vivo. The results of the studies in this proposal will provide valuable information about the potential vascular toxicity of asciminib, a novel therapy for CML, provide a more comprehensive understanding of the vascular toxicity of current BCR-ABL TKIs, and identify rapidly translatable agents to treat or prevent vascular toxicity in CML survivors.