PT  - JOURNAL ARTICLE
AU  - Phan, Carole
AU  - Seferian, Andrei
AU  - Huertas, Alice
AU  - Tu, Ly
AU  - Thuillet, Raphael
AU  - Sattler, Caroline
AU  - Le Hiress, Morane
AU  - Tamura, Yuichi
AU  - Jutant, Etienne-Marie
AU  - Chaumais, Marie-Camille
AU  - Bouchet, Stéphane
AU  - Manéglier, Benjamin
AU  - Molimard, Mathieu
AU  - Rousselot, Philippe
AU  - Sitbon, Olivier
AU  - Simonneau, Gérald
AU  - Montani, David
AU  - Humbert, Marc
AU  - Guignabert, Christophe
TI  - Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension
AID  - 10.1183/13993003.congress-2016.OA262
DP  - 2016 Sep 01
TA  - European Respiratory Journal
PG  - OA262
VI  - 48
IP  - suppl 60
4099  - http://erj.ersjournals.com/content/48/suppl_60/OA262.short
4100  - http://erj.ersjournals.com/content/48/suppl_60/OA262.full
SO  - Eur Respir J2016 Sep 01; 48
AB  - Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, an orally bioavailable dual Src/BCR/ABL tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukaemia (CML). Today, key questions remain regarding the long-term evolution of dasatinib-induced PAH and the mechanism(s) involved. Here, we demonstrate that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents, in contrast to chronic imatinib treatment. We found that rats pretreated with dasatinib, but not with imatinib, exhibit attenuated hypoxic pulmonary vasoconstriction (HPV) responses and increased susceptibility to experimental pulmonary hypertension (PH). Furthermore, in vivo and in vitro observations show that dasatinib treatment induces pulmonary endothelial cell apoptosis and induction of endoplasmic reticulum stress, in a dose dependent manner, in contrast to imatinib. We also demonstrate that dasatinib-induced endothelial cell dysfunction is mediated through production of reactive oxygen species (ROS), independently of Src family kinases. Consistently with our findings, we found significant elevations of markers of endothelial dysfunction or damage in the serum of CML patients treated with dasatinib when compared with CML patients treated with imatinib. Collectively, we report here that dasatinib causes pulmonary endothelial damage and induction of ER stress via ROS production, leading to increased susceptibility to PH development.