The Risk of Arterial Thrombosis in Patients With Chronic Myeloid Leukemia Treated With Second and Third Generation BCR-ABL Tyrosine Kinase Inhibitors May Be Explained by Their Impact on Endothelial Cells: An In-Vitro Study.

Elise Modaffari,Céline Bouvy,Jean-Michel Dogné,Anne-Sophie Delvigne,Hélène Haguet,Jonathan Douxfils,Pierre Sonveaux,Adeline Wannez

doi:10.3389/fphar.2020.01007

Abstract

BCR-ABL tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia, inducing deep molecular responses, largely improving patient survival and rendering treatment-free remission possible. However, three of the five BCR-ABL TKIs, dasatinib, nilotinib, and ponatinib, increase the risk of developing arterial thrombosis. Prior investigations reported that nilotinib and ponatinib affect the endothelium, but the mechanisms by which they exert their toxic effects are still unclear. The impact of dasatinib and bosutinib on endothelial cells has been poorly investigated. Here, we aimed to provide an in vitro homogenous evaluation of the effects of BCR-ABL TKIs on the endothelium, with a special focus on the type of cell death to elucidate the mechanisms responsible for the potential cytotoxic effects of BCR-ABL TKIs nilotinib and ponatinib on endothelial cells. We tested the five BCR-ABL TKIs at three concentrations on human umbilical venous endothelial cells (HUVECs). This study highlights the endothelial toxicity of ponatinib and provides insights about the mechanisms by which it affects endothelial cell viability. Ponatinib induced apoptosis and necrosis of HUVECs after 72 h. Dasatinib affected endothelial cells in vitro by inhibiting their proliferation and decreased wound closure as soon as 24 h of treatment and even at infra-therapeutic dose (0.005 µM). Comparatively, imatinib, nilotinib, and bosutinib had little impact on endothelial cells at therapeutic concentrations. They did not induce apoptosis nor necrosis, even after 72 h of treatment but they inhibited HUVEC proliferation. Overall, this study reports various effects of BCR-ABL TKIs on endothelial cells and suggests that ponatinib and dasatinib induce arterial thrombosis through endothelial dysfunction.

Highlights

Since the approval in 2001 of imatinib, the first tyrosine kinase inhibitor (TKI) targeting BCR-ABL, the interest and use of BCRABL tyrosine kinase inhibitors (TKIs) have continued to grow (Bhamidipati et al, 2013)
To test the cytotoxicity of BCR-ABL TKIs, human umbilical venous endothelial cells (HUVECs) were exposed to three different concentrations of imatinib mesylate, dasatinib, nilotinib, bosutinib, or ponatinib for 24 or 72 h
HUVECs exposed to imatinib at 5 μM and dasatinib at 5 and 50 nM increased their metabolism

Summary

Introduction

Since the approval in 2001 of imatinib, the first tyrosine kinase inhibitor (TKI) targeting BCR-ABL, the interest and use of BCRABL TKIs have continued to grow (Bhamidipati et al, 2013). Intolerance and resistance to imatinib arose, leading to the development and approval of dasatinib, nilotinib, and bosutinib, three second-generation BCR-ABL TKIs that are less selective for BCR-ABL than imatinib (Gorre et al, 2001; Bixby and Talpaz, 2009). These three drugs were approved for second-line treatment at the time of their approval. The five drugs are the mainstay of CML treatment (National Comprehensive Cancer Network, 2019)

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