Tyrosine Kinase Inhibitors in Pulmonary Arterial Hypertension: A Double-Edge Sword?

2013 ◽  
Vol 34 (05) ◽  
pp. 714-724 ◽  
Author(s):  
Laurent Godinas ◽  
Christophe Guignabert ◽  
Andrei Seferian ◽  
Frederic Perros ◽  
Emmanuel Bergot ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Tyrosine Kinase ◽  
Arterial Hypertension ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Double Edge ◽  
Double Edge Sword ◽  
Pulmonary Arterial

Pulmonary complications of Bcr-Abl tyrosine kinase inhibitors

2020 ◽  
Vol 56 (4) ◽  
pp. 2000279 ◽  
Author(s):  
Jason Weatherald ◽  
Louise Bondeelle ◽  
Marie-Camille Chaumais ◽  
Christophe Guignabert ◽  
Laurent Savale ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Tyrosine Kinase ◽  
Arterial Hypertension ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Chronic Myelogenous Leukaemia ◽  
Pulmonary Complications ◽  
Myelogenous Leukaemia ◽  
Dependent Manner ◽  
Pulmonary Arterial

Tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl oncoprotein revolutionised the treatment of chronic myelogenous leukaemia. Following the success of imatinib, second- and third-generation molecules were developed. Different profiles of kinase inhibition and off-target effects vary between TKIs, which leads to a broad spectrum of potential toxicities.Pulmonary complications are most frequently observed with dasatinib but all other Bcr-Abl TKIs have been implicated. Pleural effusions are the most frequent pulmonary complication of TKIs, usually associated with dasatinib and bosutinib. Pulmonary arterial hypertension is an uncommon but serious complication of dasatinib, which is often reversible upon discontinuation. Bosutinib and ponatinib have also been associated with pulmonary arterial hypertension, while imatinib has not. Rarely, interstitial lung disease has been associated with TKIs, predominantly with imatinib.Mechanistically, dasatinib affects maintenance of normal pulmonary endothelial integrity by generating mitochondrial oxidative stress, inducing endothelial apoptosis and impairing vascular permeability in a dose-dependent manner. The mechanisms underlying other TKI-related complications are largely unknown. Awareness and early diagnosis of the pulmonary complications of Bcr-Abl TKIs is essential given their seriousness, potential reversibility, and impact on future treatment options for the underlying chronic myelogenous leukaemia.

scholarly journals Incident pulmonary arterial hypertension associated with Bosutinib

2020 ◽  
Vol 10 (3) ◽  
pp. 204589402093691 ◽  
Author(s):  
Shaun Yo ◽  
John Thenganatt ◽  
Jeffrey Lipton ◽  
John Granton
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Arterial Hypertension ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Case Reports ◽  
Drug Induced ◽  
Pulmonary Arterial ◽  
Partial Reversal

Pulmonary arterial hypertension is associated with tyrosine kinase inhibitors used in the treatment of chronic myeloid leukemia. Dasatinib is a known cause of drug-induced pulmonary arterial hypertension. There have been case reports linking Bosutinib with deterioration of pre-existing pulmonary arterial hypertension. Here, we present a case of a 37-year-old woman with chronic myeloid leukemia treated with Bosutinib who was diagnosed with pulmonary arterial hypertension. Prior to Bosutinib, she had received Dasatinib without documented cardiopulmonary toxicity. Withdrawal of Bosutinib led to partial reversal of pulmonary arterial hypertension, and with the addition of pulmonary arterial hypertension-targeted treatment, there was near normalization of hemodynamics.

scholarly journals Tyrosine Kinase Inhibitor–Induced Pulmonary Arterial Hypertension

2018 ◽  
Vol 17 (2) ◽  
pp. 69-74 ◽  
Author(s):  
Mariana Preda ◽  
Andrei Seferian ◽  
Etienne-Marie Jutant ◽  
Marie-Camille Chaumais ◽  
Laurent Savale ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Tyrosine Kinase ◽  
Arterial Hypertension ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Right Heart Failure ◽  
Early Screening ◽  
Persistent Symptoms ◽  
Pulmonary Arterial ◽  
Tki Treatment

The treatment of the malignant hematological diseases has been revolutionized by the use of tyrosine kinase inhibitors (TKI): for example, imatinib in patients with chronic myeloid leukemia. Dasatinib, a second-generation TKI, has been reported to induce severe pulmonary arterial hypertension (PAH). The mechanism of PAH development is presumed to be endothelial cell toxicity through the production of mitochondrial reactive oxygen species. There are other TKIs that are reported to cause PAH, such as: ponatinib, bosutinib, lapatinib, and lorlatinib. The management of PAH due to TKIs primarily involves stopping the TKI treatment, which can lead to clinical and hemodynamic normalization. A third of the patients who develop PAH can have persistent symptoms of dyspnea and right heart failure even after the interruption of the TKIs. For these patients, use of specific PAH treatment is indicated along with close follow-up. In rare cases, TKI-induced PAH can be fatal. Thus, early screening for PAH diagnosis and proper management is required.

scholarly journals Pulmonary arterial hypertension associated with protein kinase inhibitors: a pharmacovigilance–pharmacodynamic study

2019 ◽  
Vol 53 (5) ◽  
pp. 1802472 ◽  
Author(s):  
Lucie Cornet ◽  
Charles Khouri ◽  
Matthieu Roustit ◽  
Christophe Guignabert ◽  
Marie-Camille Chaumais ◽  
...  
Keyword(s):  
Cluster Analysis ◽  
Pulmonary Arterial Hypertension ◽  
Protein Kinase ◽  
Arterial Hypertension ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
World Health ◽  
Protein Kinase Family ◽  
Kinase Family ◽  
Pulmonary Arterial

The pathophysiology of pulmonary arterial hypertension (PAH) induced by protein kinase inhibitors (PKIs) remains unclear. To gain knowledge into this rare and severe pathology we performed a study combining a pharmacovigilance approach and the pharmacodynamic properties of PKIs.A disproportionality analysis on the World Health Organization pharmacovigilance database VigiBase using the reporting odds ratio (ROR) and 95% confidence interval was first performed. Then, we identified the most relevant cellular targets of interest through a systematic literature review and correlated the pharmacovigilance signals with the affinity for the different PKIs. We further performed a hierarchical cluster analysis to assess patterns of binding affinity.A positive disproportionality signal was found for dasatinib, bosutinib, ponatinib, ruxolitinib and nilotinib. Five non-receptor protein kinases significantly correlate with disproportionality signals: c-Src (r=0.79, p=0.00027), c-Yes (r=0.82, p=0.00015), Lck (r=0.81, p=0.00046) and Lyn (r=0.80, p=0.00036), all belonging to the Src protein kinase family, and TEC (r=0.85, p=0.00006). Kinases of the bone morphogenetic protein signalling pathway also seem to play a role in the pathophysiology of PKI-induced PAH. Interestingly, the dasatinib affinity profile seems to be different from that of other PKIs in the cluster analysis.The study highlights the potential role of the Src protein kinase family and TEC in PAH induced by PKIs. This approach combining pharmacovigilance and pharmacodynamics data allowed us to generate some hypotheses about the pathophysiology of the disease; however, the results have to be confirmed by further studies.

scholarly journals A case of worsening pulmonary arterial hypertension and pleural effusions by bosutinib after prior treatment with dasatinib

2017 ◽  
Vol 7 (4) ◽  
pp. 808-812 ◽  
Author(s):  
Karan Seegobin ◽  
Amit Babbar ◽  
Jason Ferreira ◽  
Brittany Lyons ◽  
James Cury ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Kinase Inhibitors ◽  
Symptomatic Improvement ◽  
Cor Pulmonale ◽  
Chemotherapeutic Agents ◽  
Shortness Of Breath ◽  
Pleural Effusions ◽  
Pulmonary Arterial ◽  
One Year

A 52-year-old man with a past medical history of chronic myeloid leukemia (CML) in remission developed progressive shortness of breath over a two-month period. He was initially treated with dasatinib for four years, until developing pulmonary arterial hypertension (PAH) with pleural effusions. His symptoms improved after stopping dasatinib. He was then switched to bosutinib for approximately one year, which was then stopped before admission due to worsening shortness of breath. His initial workup showed bilateral pleural effusions with severe PAH and cor pulmonale. He had symptomatic improvement with PAH-specific therapy following discontinuation of the bosutinib. The life expectancy of CML patients has increased in the era of the tyrosine kinase inhibitors (TKIs), and managing adverse events (AEs) of the TKIs and improving quality of life are becoming more important. Pulmonary hypertension (PH) and pleural effusions are rarely reported AEs of bosutinib. More reports with PH and pleural effusions arising after bosutinib use in patients previously treated with dasatinib is furthermore concerning. In this era with novel chemotherapeutic agents, physicians ought to be weary of the significant morbidity implicated by these agents in the lives of patients.

scholarly journals Merit of the paper "PP2A inhibition sensitize cancer stem cells to ABL tyrosine kinase inhibition in BCR-ABL human leukemia" authored by Lai et al. [Science Translational Medicine (2019) Vol. 11, Issue 501, eaau0416, DOI: 10.1126/scitranslmed.aau0416]

2020 ◽  
Author(s):  
H.Y. Lim Tung ◽  
H.Y. Lim Tung ◽  
H.Y. Lim Tung ◽  
H.Y. Lim Tung ◽  
H.Y. Lim Tung ◽  
...  
Keyword(s):  
Stem Cells ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Enzyme Regulation ◽  
Human Leukemia ◽  
Abl Tyrosine Kinase ◽  
Important Principle ◽  
Double Edge ◽  
Double Edge Sword ◽  
Blast Cells

The paper by Lai et al. [1] showed that inhibition of PP-2A with LB100 or LB102 in conjunction with Tyrosine kinase Inhibitors (TKIs) was effective at targeting BCR-ABL + blast cells and insensitive leukemic stem cells (LSCs). Perotti et al. [2] has severely criticised the paper by Lai et al [2]. However, Perotti et al. [2] has failed to appreciate an important principle of the role of PP-2A as a tumor suppressor and its regulation in the cell, namely that in general, PP-2A dephosphoryltes and inactivates enzymes and proteins that upregulate cell proliferation, cell survival, tumorigenic and metastasizing pathways but with a limited number of of enzymes and proteins, PP-2A acts to upregulate them. Thus, PP-2A is a double-edge sword and modulation of its activity must be calibrated empirically. Also, Perotti et al. [2] has misunderstood an important principle of enzyme regulation, namely that PP-2A is regulated by inhibitory and activating molecules and not through "targeting proteins" which has not been scientifically verified. It is submitted that the paper by Lai et al. [1] has strong merit as it shows for the first time that an inhibitor of PP-2A can synergize with a TKI.

Sign in / Sign up

Export Citation Format

Share Document