Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension

作者：Guignabert Christophe; Phan Carole; Seferian Andrei; Huertas Alice; Tu Ly; Thuillet Raphael; Sattler Caroline; Le Hiress Morane; Tamura Yuichi; Jutant Etienne Marie; Chaumais Marie Camille; Bouchet Stephane; Maneglier Benjamin; Molimard Mathieu; Rousselot Philippe; Sitbon Olivier; Simonneau Gerald; Montani David; Humbert Marc

来源：Journal of Clinical Investigation, 2016, 126(9): 3207-3218.

DOI：10.1172/JCI86249

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 hypertenslon (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.

• 出版日期2016-9