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

Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension

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 2

Dasatinib treatment causes pulmonary EC dysfunction in vivo.

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Dasatinib treatment causes pulmonary EC dysfunction in vivo. (A) Values ...
(A) Values of mean pulmonary arterial pressure (mPAP) in vehicle-, dasatinib-, and imatinib-treated rats while ventilated with room air (baseline) and after 10 minutes of ventilation with a hypoxic gas mixture (acute Hypoxia [Hx]). mPAP increased in rats treated with vehicle, dasatinib (1×), and imatinib, but not in rats treated with dasatinib (10×). (B) Quantification of the circulating levels of soluble forms of ICAM-1 (sICAM-1), VCAM-1 (sVCAM-1), and E-selectin (sE-selectin) in vehicle-, dasatinib-, and imatinib-treated rats. (C) Confocal microscopic analyses and double labeling with ICAM-1, VCAM-1, and E-selectin with the endothelial-specific marker Tie2 in lungs of vehicle-, dasatinib-, and imatinib-treated rats. (D and E) Representative Western blots and quantification of the glucose-regulated protein 78 (GRP78)/β-actin ratio (D) and of the cleaved activating transcription factor 6 (ATF6)/β-actin ratio, the X-box–binding protein 1 (XBP1)/β-actin ratio, and the phospho–eukaryotic initiation factor 2α (eIF2α)/eIF2α ratio (E) in lungs of vehicle-, dasatinib-, and imatinib-treated rats. Horizontal lines display the mean ± SEM (n = 4–9). *P < 0.05, **P < 0.01, ***P < 0.001 vs. vehicle-treated rats or baseline; #P < 0.05, ##P < 0.01 vs. rats treated with dasatinib (10×). Scale bars: 20 μm. HPV, hypoxic pulmonary vasoconstriction; L, lumen.