Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension

Guignabert, Christophe; Phan, Carole; Seferian, Andrei; Huertas, Alice; Tu, Ly; Thuillet, Raphaël; Sattler, Caroline; Hiress, Morane Le; Tamura, Yuichi; Jutant, Étienne-Marie; Chaumais, Marie-Camille; Bouchet, Stéphane; Manéglier, Benjamin; Molimard, Mathiéu; Rousselot, Philippe; Sitbon, Olivier; Simonneau, Gérald; Montani, David; Humbert, Marc

doi:10.1172/jci86249

Cited by 203 publications

(186 citation statements)

References 47 publications

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“…As our two cases of bosutinib-associated PAH occurred in patients with prior dasatinib-induced PAH, we cannot exclude that these cases were potentiated or facilitated by the prior use of dasatinib. This hypothesis is in accordance with our recent results showing that dasatinib may increase the risk of developing pulmonary hypertension in animal models in the presence of a second "hit" (monocrotaline or chronic hypoxia) [10].…”

supporting

confidence: 93%

“…As dasatinib, ponatinib and bosutinib are also known inhibitors of Src tyrosine kinase, it is conceivable that this pathway may be implicated in TKI-induced PAH. However, dasatinib-mediated apoptosis in pulmonary endothelial cells is not dependent of Src kinase inhibition [10]. In addition, bosutinib is a known potent inhibitor of fibroblast growth factor receptor and mitogen-activated protein kinases that are known signalling pathways involved in endothelial cell survival [12,13], therefore we hypothesise that a potential mechanism could be the apoptosis of endothelial cells.…”

mentioning

confidence: 93%

“…Dasatinib may also induce PAH with an estimated lowest incidence of PAH of 0.45% [3]. We recently demonstrated that dasatinib causes pulmonary vascular damage through mitochondrial reactive oxygen species production in a dose-dependent manner, leading to increased susceptibility to develop PAH [10]. Unique to dasatinib-associated PAH (e.g.…”

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confidence: 99%

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Deterioration of pulmonary hypertension and pleural effusion with bosutinib following dasatinib lung toxicity

et al. 2016

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Tyrosine kinase inhibitors (TKIs) targeting BCR/ABL such as imatinib, nilotinib, dasatinib, bosutinib and ponatinib have revolutionised the management of patients with chronic myeloid leukaemia (CML) [1]. Pleural effusions and pulmonary arterial hypertension (PAH) have been reported in patients treated with these agents [2][3][4]. These side-effects are more frequently observed with dasatinib use, with partial or complete reversibility after drug withdrawal [3]. Bosutinib is a second-generation TKI prescribed in case of intolerance or resistance to imatinib, nilotinib or dasatinib. In the present report, we describe two cases of worsening of dasatinib-induced PAH and two cases of severe pleural effusions, suggesting overlapping pulmonary toxicity of bosutinib and dasatinib.Patient 1, a 44-year-old Caucasian woman with CML, was successively treated with hydroxycarbamide, imatinib, nilotinib and dasatinib. After 3 years on dasatinib, she complained of exertional dyspnoea, New York Heart Association functional class (NYHA FC) II. Echocardiography showed a dilated right ventricle and an estimated systolic pulmonary artery pressure (PAP) of 80 mmHg. Right heart catheterisation demonstrated pre-capillary pulmonary hypertension (mean PAP 34 mmHg, pulmonary capillary wedge pressure (PCWP) 9 mmHg, cardiac index (CI) 3.8 L·min

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Deterioration of pulmonary hypertension and pleural effusion with bosutinib following dasatinib lung toxicity

et al. 2016

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“…The mechanism appears to be related to dasatinib-mediated smooth muscle proliferation and vasoconstriction through inhibition of the Src kinases. 29 Until more information is known about the specific risk factors, our recommendation is to avoid using dasatinib for treatment of CML if possible and to choose another TKI for treatment of CML.…”

Section: Beyond Stimulants: Dasatanib and Phmentioning

confidence: 99%

Drug-Induced Pulmonary Hypertension: The First 50 Years

Perez

2017

Advances in Pulmonary Hypertension

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Drug-induced pulmonary arterial hypertension (D-PAH) is a form of World Health Organization Group 1 pulmonary hypertension (PH) characterized by severe small vessel loss and obstructive vasculopathy, which leads to progressive right heart failure and death. To date, 16 different compounds have been associated with D-PAH, including anorexinogens, recreational stimulants, and more recently, several Food and Drug Administration–approved medications. While the clinical manifestations, pathology, and hemodynamic profile of D-PAH are indistinguishable from other forms of PAH, its clinical course can be unpredictable and largely dependent on removal of the offending agent. Since only a subset of individuals develop D-PAH, it is likely that genetic susceptibility plays a role in pathogenesis, but characterization of the genetic factors responsible for disease susceptibility remains incomplete. Besides aggressive treatment with PH-specific therapies, the major challenge in the management of D-PAH remains the early identification of compounds capable of injuring the pulmonary circulation in susceptible individuals. Institution of pharmacovigilance, precision medicine strategies, and global warning systems will help facilitate identification of high-risk drugs and institute regulation strategies to prevent further outbreaks of D-PAH.

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“…However, as suggested by LEHMANN et al [18], senescence seems to predominate in epithelial cells in IPF; therefore, elimination of senescent antifibrotic fibroblasts should not be a limiting factor. Secondly, dasatinib was recently shown to induce pulmonary endothelial damage, with an increased susceptibility to pulmonary hypertension in rodent experimental models and in patients with chronic myeloid leukaemia treated with dasatinib [33]. Since pulmonary hypertension is a well-recognised comorbidity in IPF [34], the use of dasatinib in IPF patients could have potential aggravating effects in the long term.…”

mentioning

confidence: 99%