Journal Article

Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension

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

2016

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adult / Animals / Antineoplastic Agents - adverse effects / Antineoplastic Agents - pharmacology / Apoptosis / Biomedical research / Cardiology and cardiovascular system / Cells, Cultured / Cellular Biology / Dasatinib / Dasatinib - adverse effects / Dasatinib - pharmacology / Drug dosages / E-Selectin - blood / Experiments / Female / Genetic Predisposition to Disease / Grants / Health aspects / Hemodynamics / Human health and pathology / Humans / Hypertension, Pulmonary - chemically induced / Hypoxia / Hypoxia - metabolism / Imatinib Mesylate - pharmacology / Intercellular Adhesion Molecule-1 - blood / Laboratory animals / Leukemia / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology / Life Sciences / Lung - blood supply / Lung - drug effects / Male / Middle Aged / Mitochondria - metabolism / Mortality / Pulmonary hypertension / Pulmonology and respiratory tract / Rats / Reactive Oxygen Species - metabolism / Risk factors / Rodents / Scholarships & fellowships / Toxicity / Vascular Cell Adhesion Molecule-1 - blood