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BCR-ABL1 inhibitors decrease cholesterol and atherosclerosis, and activate coagulation in a translational mouse model

ABSTRACT: Objectives: Treatment with the second and third generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) increases cardiovascular risk in chronic myeloid leukemia (CML) patients. We investigated the multifactorial process of TKI-induced vascular adverse effects in a translational model for atherosclerosis, the APOE3*Leiden.CETP mouse. Approach and results: Mice were treated for sixteen weeks with imatinib (150 mg/kg BID), nilotinib (10 and 30 mg/kg QD) or ponatinib (3 and 10 mg/kg QD), giving similar drug exposures as in CML-patients. Cardiovascular risk factors were analyzed throughout the study, and histopathological analysis of atherosclerosis and transcriptome analysis of the liver was performed. Imatinib and ponatinib decreased plasma cholesterol (imatinib, -69%, :<0.001; ponatinib 3mg/kg, -37%, P<0.001; ponatinib 10 mg/kg -44%, P<0.001) and atherosclerotic lesion area (imatinib, -78%, P<0.001; ponatinib 3 mg/kg, -52%, P=0.014; ponatinib 10 mg/kg, -48%, P=0.001), which were not affected by nilotinib. In addition, imatinib increased plaque stability. Gene expression and pathway analysis predicted that ponatinib may lead to a pro-coagulant state by adversely affecting coagulation factors of both the contact activation (intrinsic) and tissue factor (extrinsic) pathways. The coagulation factor VII in plasma was increased by ponatinib, whereas nilotinib increased FVIIa. Conclusion: Imatinib showed a beneficial cardiovascular risk profile, whereas nilotinib and ponatinib increase the cardiovascular risk through induction of a pro-thrombotic state.

ORGANISM(S): Mus musculus

PROVIDER: GSE103908 | GEO | 2018/05/24

REPOSITORIES: GEO

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