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Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension
Christophe Guignabert, … , David Montani, Marc Humbert
Christophe Guignabert, … , David Montani, Marc Humbert
Published September 1, 2016; First published August 2, 2016
Citation Information: J Clin Invest. 2016;126(9):3207-3218. https://doi.org/10.1172/JCI86249.
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Categories: Research Article Vascular biology

Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension

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Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development.

Authors

Christophe Guignabert, Carole Phan, Andrei Seferian, Alice Huertas, Ly Tu, Raphaël Thuillet, Caroline Sattler, Morane Le Hiress, Yuichi Tamura, Etienne-Marie Jutant, Marie-Camille Chaumais, Stéphane Bouchet, Benjamin Manéglier, Mathieu Molimard, Philippe Rousselot, Olivier Sitbon, Gérald Simonneau, David Montani, Marc Humbert

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Figure 1

Pretreatment of rats with dasatinib confers an exaggerated response to monocrotaline (MCT) and chronic hypoxia (CHx), 2 inducers of experimental pulmonary hypertension in vivo.

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Pretreatment of rats with dasatinib confers an exaggerated response to m...
(A) Rodent models used to study the in vivo effects of dasatinib on pulmonary hemodynamic parameters and vascular remodeling: chronic treatment group (group A) and pretreatment group (group B). (B–D) Values of mean pulmonary arterial pressure (PAP) (B), Fulton index (C), and cardiac output (D) in vehicle-, dasatinib-, and imatinib-treated rats. (E) Representative images of H&E- and α-smooth muscle (SM) actin–stained sections of distal pulmonary arteries in vehicle-, dasatinib-, and imatinib-treated rats. (F and G) Quantification of the percentage of muscularized pulmonary arteries (F) and wall thickness (G) in lungs of vehicle-, dasatinib-, and imatinib-treated rats. Horizontal lines display the mean ± SEM (n = 5–6). **P < 0.01, ***P < 0.001 vs. vehicle-treated rats; #P < 0.05, ##P < 0.01, ###P < 0.001 vs. vehicle-treated rats exposed to MCT or to CHx. Scale bars: 20 μm.
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