Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target site
- PMID: 28757617
- PMCID: PMC5669463
- DOI: 10.1038/leu.2017.245
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 hindlimb-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.
Conflict of interest statement
E.H. received honoraria from Novartis. G.H.S. received honoraria from Amgen, Astra Zeneca, Boehringer Ingelheim, BMS, Elli Lilly, Merck, Novo-Nordisk, Novartis, Pfizer, and Sanofi-Aventis. D.W. received honoraria from Pfizer, BMS, Novartis, and Ariad and Research Grants from Pfizer and Ariad. R.K. received honoraria from Ariad and a Research Grant from Ariad. G.H. received honoraria form Novartis and Ariad. P.V. received honoraria from Novartis, Celgene, Pfizer, Deciphera, BMS, Ariad, and Incyte; and research grants from Novartis, Deciphera, and Ariad. The other authors declare no competing financial interests.
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