Chronic Myeloid Leukemia (CML) is a type of cancer that affects the blood and bone marrow and is commonly treated with drugs known as BCR-ABL1 tyrosine kinase inhibitors (TKIs).

Nilotinib, one such TKI, is recognized for its effectiveness against CML, but it is also associated with a concerning side effect: 23.5% of patients taking nilotinib experience vascular adverse effects, collectively known as nilotinib-induced arterial disease (NAD). And the reasons why this happens are now unclear.

A recent study using human induced pluripotent stem cells (hiPSCs) sheds light on why nilotinib causes arterial disease, providing crucial insights that could help develop safer treatments.

Researchers utilized hiPSCs to generate endothelial cells and vascular smooth muscle cells (VSMCs) to delineate the specific cellular targets of nilotinib’s vascular effects.

They discovered that nilotinib adversely affects endothelial cell functions such as proliferation and migration, and increases intracellular nitric oxide, but it does not significantly impact lipid uptake or endothelial barrier function (as measured by Nanion’s impedance technology).

In contrast, nilotinib did not affect VSMCs, indicating that NAD is primarily mediated through endothelial cells.

One of the critical aspects of the study was determining whether the side effects were due to nilotinib’s intended target, the ABL1 protein. By employing ABL1 knockout models, researchers demonstrated that the adverse effects on endothelial cells persisted even in the absence of ABL1, suggesting that they are due to off-target effects of nilotinib rather than direct inhibition of ABL1.

These findings are significant for several reasons.

First, they provide a clear direction for developing new TKIs that can treat CML without causing harmful vascular side effects. Since the adverse effects are not linked to the inhibition of ABL1, future drugs can be designed to avoid these off-target interactions while still effectively targeting the ABL1 protein.

Moreover, this study highlights the usefulness of hiPSC-derived cells as a model for investigating drug-induced vascular effects. Such models can accelerate our understanding of how drugs affect the vasculature and lead to quicker advancements in creating safer medications.

In conclusion, while nilotinib remains a potent treatment for CML, its vascular side effects pose significant challenges. This study provides a promising approach to overcoming these challenges, paving the way for the development of safer and equally effective alternatives.

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Find the original article here: https://www.nature.com/articles/s41598-024-57686-8

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