Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target site

Abstract

The BCR/ABL1 inhibitor Nilotinib is increasingly used to treat patients with chronic myeloid leukemia (CML). Although otherwise well-tolerated, Nilotinib has been associated with the occurrence of progressive arterial occlusive disease (AOD). Our objective was to determine the exact frequency of AOD and examine in vitro and in vivo effects of Nilotinib and Imatinib on endothelial cells to explain AOD-development. In contrast to Imatinib, Nilotinib was found to upregulate pro-atherogenic adhesion-proteins (ICAM-1, E-selectin, VCAM-1) on human endothelial cells. Nilotinib also suppressed endothelial cell proliferation, migration and tube-formation, and bound to a distinct set of target-kinases, relevant to angiogenesis and atherosclerosis, including angiopoietin receptor-1 TEK, ABL-2, JAK1, and MAP-kinases. Nilotinib and siRNA against ABL-2 also suppressed KDR expression. In addition, Nilotinib augmented atherosclerosis in ApoE-/- mice and blocked reperfusion and angiogenesis in a hind-limb-ischemia model of arterial occlusion, whereas Imatinib showed no comparable effects. Clinically overt AOD-events were found to accumulate over time in Nilotinib-treated patients. After a median observation-time of 2.0 years, the AOD-frequency was higher in these patients (29.4%) compared to risk factor- and age-matched controls (<5%). Together, Nilotinib exerts direct pro-atherogenic and anti-angiogenic effects on vascular endothelial cells, which may contribute to development of AOD in patients with CML.

Ponatinib in the Treatment of Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Leukemia: Recommendations of a German Expert Consensus Panel with Focus on Cardiovascular Management

“…The pathophysiological mechanisms underlying the vascular toxicity of TKIs have not been clearly established but are believed to overlap to some extent. In a mouse model of atherosclerosis, nilotinib was shown to have directly proatherogenic effects on endothelial cells [42]. Nilotinib also caused metabolic changes including elevation of cholesterol and fasting glucose levels [42].…”

Republished: Tyrosine kinase inhibitor induced rapidly progressive vasculopathy after intracranial stent placement

“…These include increased fasting glucose, type 2 diabetes mellitus, and increased total high density and low density lipoprotein cholesterol. Nilotinib also interferes with endothelial cell migration, cell proliferation, and promotes a pro-atherogenic phenotype by increasing the expression of cell surface adhesion molecules 7. A recent paper revealed multiple pathways through which Nilotinib encourages a prothrombotic state 8.…”

Monocyte subsets and their phenotypes during treatment with BCR‐ABL1 tyrosine kinase inhibitors for Philadelphia chromosome‐positive leukemia

“…Although these TKIs have been reported to be well tolerated during long‐term treatment, recent studies have demonstrated that severe vascular events, such as coronary artery disease (CAD), cerebral ischemic disease, and peripheral artery occlusive disease, have developed in some patients receiving each TKI . The exact mechanisms for development of vascular events during treatment of TKIs remain unclear, but recent data suggested that the direct effects of vascular endothelial cells on TKIs might contribute to the development of vascular events …”

“…[1][2][3] The exact mechanisms for development of vascular events during treatment of TKIs remain unclear, but recent data suggested that the direct effects of vascular endothelial cells on TKIs might contribute to the development of vascular events. [3][4][5] Atherosclerosis is characterized as vascular inflammation involving endothelial cells, smooth muscle cells, lymphocytes, and monocytes/ macrophages. The inflammatory response for development of atherosclerosis is mainly associated with recruitment and activation of monocytes and monocyte-derived macrophages on atherosclerotic plaques.…”