Background: Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF) which remains poorly understood.
Methods: We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacologic experiments. The pharmacovigilance database, VigiBase((R)) was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF.
Results: We demonstrate that treatment of mice with ibrutinib for four weeks results in inducible AF, left atrial enlargement, myocardial fibrosis and inflammation. This effect was reproduced in mice lacking BTK but not in mice treated with four-weeks of acalabrutinib, a more specific BTK inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving C-terminal src kinase (CSK) as the strongest candidate for ibrutinib induced AF. Cardiac specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in Vigibase((R)) confirmed increased reporting of AF associated with kinase inhibitors blocking Csk vs non-Csk inhibitors, with a reporting odds-ratio of 8.0 [95% CI 7.3-8.7, p<0.0001].
Conclusions: These data identify Csk inhibition as the mechanism by which ibrutinib leads to AF.
Clinical Trial Registration: URL: www.clinicaltrials.
gov Unique Identifier: NCT03530215.
|投稿者||Xiao, Ling; Salem, Joe-Elie; Clauss, Sebastian; Hanley, Alan; Bapat, Aneesh; Hulsmans, Maarten; Iwamoto, Yoshiko; Wojtkiewicz, Gregory; Cetinbas, Murat; Schloss, Maximilian J; Tedeschi, Justin; Lebrun-Vignes, Benedicte; Lundby, Alicia; Sadreyev, Ruslan I; Moslehi, Javid J; Nahrendorf, Matthias; Ellinor, Patrick T; Milan, David J|
|組織名||Cardiovascular Research Center, Massachusetts General Hospital and Harvard;Medical School, Boston, MA.;Clinical Pharmacology, Sorbonne University, INSERM, APHP, UNICO-GRECO;Cardio-oncology Program, Hospital Pitie-Salpetriere, Paris, France; Clinical;Investigation Center, Paris, France; Vanderbilt University Medical Center,;Cardio-Oncology Program, Division of Cardiovascular Medicine, Nashville, TN.;Medical School, Boston, MA; Department of Medicine I, Klinikum Grosshadern,;University of Munich (LMU), Munich, Germany; DZHK (German Centre for;Cardiovascular Research), Partner site Munich, Munich Heart Alliance (MHA),;Munich, Germany.;Center for Systems Biology, Department of Radiology, Massachusetts General;Hospital and Harvard Medical School, Boston, MA.;Department of Molecular Biology, Massachusetts General Hospital and Harvard;Medical School, Boston, MA; Department of Genetics, Harvard Medical School,;Boston, MA.;Cardio-oncology Program, Hospital Pitie-Salpetriere, Paris, France; Universite;Paris Est (UPEC), IRMB- EA 7379 EpiDermE (Epidemiology in Dermatology and;Evaluation of therapeutics), F-94010, Creteil, France; Clinical Pharmacology and;Regional Pharmacovigilance Center, Sorbonne University, ISERM, APHP, UNICO-GRECO;Cardiooncology Program, Hospital Pitie-Salpetriere, Paris, France.;Department of Biomedical Sciences, Faculty of Health and Medical Sciences and NNF;Center for Protein Research, Kobenhavns Universitet, Copenhagen, Denmark.;Medical School, Boston, MA; Department of Pathology, Massachusetts General;Vanderbilt University Medical Center, Cardio-Oncology Program, Division of;Cardiovascular Medicine, Nashville, TN.;Medical School, Boston, MA; Center for Systems Biology, Department of Radiology,;Massachusetts General Hospital and Harvard Medical School, Boston, MA.;Medical School, Boston, MA; Cardiovascular Disease Initiative, Broad Institute of;Harvard and MIT, Cambridge, MA.;Medical School, Boston, MA; Leducq Foundation, Boston MA.|