BCR-ABL Tyrosine Kinase Inhibitors: Which Mechanism(s) May Explain the Risk of Thrombosis?

Abstract

Imatinib, the first-in-class BCR-ABL tyrosine kinase inhibitor (TKI), had been a revolution for the treatment of chronic myeloid leukemia (CML) and had greatly enhanced patient survival. Second- (dasatinib, nilotinib, and bosutinib) and third-generation (ponatinib) TKIs have been developed to be effective against BCR-ABL mutations making imatinib less effective. However, these treatments have been associated with arterial occlusive events. This review gathers clinical data and experiments about the pathophysiology of these arterial occlusive events with BCR-ABL TKIs. Imatinib is associated with very low rates of thrombosis, suggesting a potentially protecting cardiovascular effect of this treatment in patients with BCR-ABL CML. This protective effect might be mediated by decreased platelet secretion and activation, decreased leukocyte recruitment, and anti-inflammatory or antifibrotic effects. Clinical data have guided mechanistic studies toward alteration of platelet functions and atherosclerosis development, which might be secondary to metabolism impairment. Dasatinib, nilotinib, and ponatinib affect endothelial cells and might induce atherogenesis through increased vascular permeability. Nilotinib also impairs platelet functions and induces hyperglycemia and dyslipidemia that might contribute to atherosclerosis development. Description of the pathophysiology of arterial thrombotic events is necessary to implement risk minimization strategies.

Keywords: BCR-ABL; arterial thrombotic events; chronic myeloid leukemia; tyrosine kinase inhibitors.

Fig. 1

Signaling pathways supporting platelet adhesion, activation, and aggregation. Tyrosine kinases are involved in several pathways and contribute to platelet adhesion, aggregation, and activation. Important players in platelet signaling are members of the Src family kinases; particularly Lyn, Fyn, and cSRC. These three tyrosine kinases are inhibited by dasatinib which might explain platelet dysfunction encountered with this treatment. Additionally, dasatinib also inhibits BTK, Syk, EphA4, and EphB1—four tyrosine kinases involved in platelet activation and aggregate stabilization. 5HT, 5-hydroxytryptamine; ADP, adenosine diphosphate; Btk, Bruton's tyrosine kinase; Ca, calcium; Eph, ephrin; FcR, Fc receptor; GP, glycoprotein; PAR, protease-activated receptor; PI3K, phosphoinositide 3-kinase; PLC, phospholipase C; TXA2, thromboxane A2; vWF, Von Willebrand factor.

Fig. 2

Effects of BCR-ABL TKIs on glucose metabolism. Imatinib and dasatinib possess hypoglycemic effects, whereas nilotinib increases blood glucose level and diabetes development. The figure describes glucose metabolism and boxes contain emitted hypotheses for effects of imatinib, dasatinib, and nilotinib on glucose metabolism. Four major hypotheses have been emitted including impact on insulin production by β-cells, β-cell survival, peripheral insulin sensitivity, and hepatic glucose production. ABL, Abelson; FAK, focal adhesion kinase; GLUT, glucose transporter; IRS-1, insulin receptor substrate 1; JNK, c-Jun N-terminal kinases; MEKK1, MAPK/ERK kinase kinase 1; NF-κB, nuclear factor-kappa B; PDK1, pyruvate dehydrogenase kinase 1; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species.

Fig. 3

Effects of BCR-ABL TKIs on lipid metabolism. Several hypotheses have been emitted to explain the imatinib-induced hypolipidemic effect. Imatinib regulates expression of genes involved in lipid metabolism: Apobec1 that regulates ApoB expression through the introduction of a stop codon into ApoB mRNA (ApoB is essential for VLDL production), and LDLR that is implicated in lipid clearance. Imatinib-induced PDGFR inhibition influences LPL synthesis and dysregulates LRP. Dasatinib and nilotinib increase cholesterol plasma level through an unknown mechanism. Global hypotheses can be emitted and include increased hepatic lipid synthesis (possibly related to hyperinsulinemia) and decreased lipid clearance through LDLR functional defect or decreased LPL synthesis. ABC, ATP-binding cassette; C, cholesterol; CETP, cholesteryl ester transfer protein; CM, chylomicron; FA, fatty acid; HMGCoA reductase, hydroxymethylglutaryl-CoA reductase; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LPL, lipoprotein lipase; LRP, lipoprotein receptor-related protein; PDGFR, platelet-derived growth factor receptor; VLDL, very low-density lipoprotein.

Fig. 4

Specificity of imatinib, dasatinib, nilotinib, and ponatinib toward tyrosine kinases. Green, yellow, red, and blue circles contain tyrosine kinase inhibited by dasatinib, nilotinib, bosutinib, and ponatinib, respectively. Tyrosine kinases in white represent imatinib off-targets. This figure summarizes results from 13 experiments. In case of conflictual results between studies, a conservative approach has been applied. Additional information is provided in the Supplementary Material .