The BCR-ABL1 Inhibitors Imatinib and Ponatinib Decrease Plasma Cholesterol and Atherosclerosis, and Nilotinib and...

Area of Science:

• Cardiovascular Pharmacology
• Oncology
• Translational Medicine

Background:

• Second and third-generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) are associated with increased cardiovascular risk in chronic myeloid leukemia (CML) patients.
• Understanding the specific vascular adverse effects of different TKI generations is crucial for patient safety.
• The APOE*3Leiden.CETP mouse model offers a translational platform for investigating atherosclerosis and TKI-induced vascular effects.

Purpose of the Study:

• To investigate the vascular adverse effects of imatinib, nilotinib, and ponatinib (three generations of TKIs) in a translational atherosclerosis model.
• To evaluate the impact of these TKIs on cardiovascular risk factors, atherosclerosis progression, and plaque stability.
• To elucidate the molecular mechanisms underlying TKI-induced cardiovascular risk, focusing on liver gene expression and coagulation pathways.

Main Methods:

• Treatment of APOE*3Leiden.CETP mice with imatinib, nilotinib, or ponatinib for sixteen weeks at clinically relevant exposures.
• Longitudinal analysis of cardiovascular risk factors, including plasma cholesterol levels.
• Histopathological assessment of atherosclerotic lesion area and plaque stability, alongside liver transcriptome analysis and coagulation factor assessment.

Main Results:

• Imatinib and ponatinib significantly decreased plasma cholesterol and atherosclerotic lesion area, with imatinib also improving plaque stability.
• Nilotinib did not affect cholesterol levels or atherosclerotic lesion size.
• Ponatinib upregulated pro-coagulant factors, and both nilotinib and ponatinib were associated with a pro-thrombotic state, indicated by altered FVII and FVIIa levels.

Conclusions:

• Imatinib demonstrated a beneficial cardiovascular risk profile in this translational model.
• Nilotinib and ponatinib, however, increased cardiovascular risk by inducing a pro-thrombotic state.
• These findings highlight the differential vascular safety profiles of TKIs and emphasize the need for careful cardiovascular monitoring in CML patients.