Abstract
Purpose
Pulmonary arterial hypertension (PAH) results from occlusion or vasoconstriction of pulmonary vessels, leading to progressive right ventricular failure. Dasatinib, a BCR-ABL1 tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myelogenous leukemia, has been associated with PAH. In contrast, the BCR-ABL1 TKI imatinib has demonstrated anti-vasoproliferative properties and has been investigated as a potential treatment for PAH. Here we describe studies evaluating the effects of dasatinib and imatinib on cardiovascular and pulmonary functions to understand the reported differential consequences of the two TKIs in a clinical setting.
Methods
The direct effects of dasatinib and imatinib were explored in vivo to investigate possible mechanisms of dasatinib-induced PAH. In addition, effects of dasatinib and imatinib on PAH-related mediators were evaluated in vitro.
Results
In rats, both TKIs increased plasma nitric oxide (NO), did not induce PAH-related structural or molecular changes in PA or lungs, and did not alter hemodynamic lung function compared with positive controls. Similarly, in the pulmonary artery endothelial cells and smooth muscle cells co-culture model, imatinib and dasatinib increased NO and decreased endothelin-1 protein and mRNA.
Conclusions
The results of these studies indicated that dasatinib did not induce physiological changes or molecular signatures consistent with PAH when compared to positive controls. Instead, dasatinib induced changes consistent with imatinib. Both dasatinib and imatinib induced biochemical and structural changes consistent with a protective effect for PAH. These data suggest that other factors of unclear etiology contributed to the development of PAH in patients treated with dasatinib.
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Acknowledgements
Professional medical writing support was provided by Beverly E. Barton, PhD, of StemScientific, an Ashfield Company, funded by Bristol-Myers Squibb. The authors thank Dr Dezhi Xing and Mr George Thalody for their contributions to the preclinical experiments.
Author contributions
All authors provided guidance on the analysis and interpretation of the results, contributed to the drafting and critical review of the manuscript, and provided final approval for submission. NW provided clinical input; JW provided the histopathological evaluations; MG, JH, JL, DS, RTB, MG, TS, and BB helped design and interpret the preclinical experiments; JH, JL, and BB performed the preclinical experiments; DS, NW, and RTB analyzed the data.
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This study was funded by Bristol-Myers Squibb.
Conflict of interest
The authors take full responsibility for the content of this publication and confirm that it reflects their viewpoint and expertise. The authors did not receive financial compensation for authoring the manuscript. Bethany Baumgart, James Hennan, Julia Li, Michael Graziano, Thomas Sanderson, and Roderick Todd Bunch are employees of Bristol-Myers Squibb. James Hennan, Jochen Woicke, Michael Graziano, Nicola Wallis, Thomas Sanderson, and Roderick Todd Bunch received equity from Bristol-Myers Squibb as part of employee compensation. Mausumee Guha, Damir Simic, Jochen Woicke, and Nicola Wallis were employees of Bristol-Myers Squibb at the time the study was conducted and data analyzed.
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Animal studies were conducted in compliance with the USDA Animal Welfare Act and were approved by the Institutional Animal Care and Use Committee.
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B. Baumgart and M. Guha contributed equally to this work.
M. Guha, J. Woicke, D. Simic and N. Wallis: Employee of Bristol-Myers Squibb at the time the study was conducted and data analyzed.
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Baumgart, B., Guha, M., Hennan, J. et al. In vitro and in vivo evaluation of dasatinib and imatinib on physiological parameters of pulmonary arterial hypertension. Cancer Chemother Pharmacol 79, 711–723 (2017). https://doi.org/10.1007/s00280-017-3264-2
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DOI: https://doi.org/10.1007/s00280-017-3264-2