Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension

J Clin Invest. 2016 Sep 1;126(9):3207-18. doi: 10.1172/JCI86249. Epub 2016 Aug 2.


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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Cells, Cultured
  • Dasatinib / adverse effects*
  • Dasatinib / pharmacology
  • E-Selectin / blood
  • Female
  • Genetic Predisposition to Disease
  • Hemodynamics
  • Humans
  • Hypertension, Pulmonary / chemically induced*
  • Hypoxia / metabolism
  • Imatinib Mesylate / pharmacology
  • Intercellular Adhesion Molecule-1 / blood
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Lung / blood supply*
  • Lung / drug effects*
  • Male
  • Middle Aged
  • Mitochondria / metabolism
  • Rats
  • Reactive Oxygen Species / metabolism
  • Vascular Cell Adhesion Molecule-1 / blood


  • Antineoplastic Agents
  • E-Selectin
  • Reactive Oxygen Species
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • Imatinib Mesylate
  • Dasatinib