Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase
Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood. We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemopr...
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Published in | Circulation (New York, N.Y.) Vol. 142; no. 25; pp. 2443 - 2455 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Heart Association
22.12.2020
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Subjects | |
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Abstract | Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood.
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 pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF.
We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase 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 CSK (C-terminal Src kinase) 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 confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3-8.7;
<0.0001).
These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov; Unique identifier: NCT03530215. |
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AbstractList | Background:Ibrutinib is a Bruton tyrosine kinase 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 pharmacological experiments. The pharmacovigilance database, VigiBase, 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 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase 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 CSK (C-terminal Src kinase) 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 confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus 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 through which ibrutinib leads to AF. Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood. 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 pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF. We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase 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 CSK (C-terminal Src kinase) 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 confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3-8.7; <0.0001). These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov; Unique identifier: NCT03530215. Background: Ibrutinib is a Bruton tyrosine kinase 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 pharmacological experiments. The pharmacovigilance database, VigiBase, 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 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase 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 CSK (C-terminal Src kinase) 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 confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus 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 through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov ; Unique identifier: NCT03530215. BACKGROUNDIbrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood. METHODSWe 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 pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF. RESULTSWe demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase 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 CSK (C-terminal Src kinase) 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 confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3-8.7; P<0.0001). CONCLUSIONSThese data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov; Unique identifier: NCT03530215. |
Author | Lundby, Alicia Bapat, Aneesh Moslehi, Javid Lebrun-Vignes, Bénédicte Sadreyev, Ruslan I Ellinor, Patrick T Clauss, Sebastian Milan, David J Hulsmans, Maarten Cetinbas, Murat Iwamoto, Yoshiko Nahrendorf, Matthias Schloss, Maximilian J Tedeschi, Justin Xiao, Ling Salem, Joe-Elie Hanley, Alan Wojtkiewicz, Gregory |
Author_xml | – sequence: 1 givenname: Ling surname: Xiao fullname: Xiao, Ling organization: Cardiovascular Research Center (L.X., S.C., A.H., A.B., J.T., M.N., P.T.E., D.J.M.), Massachusetts General Hospital and Harvard Medical School, Boston, MA – sequence: 2 givenname: Joe-Elie surname: Salem fullname: Salem, Joe-Elie organization: Vanderbilt University Medical Center, Cardio-Oncology Program, Division of Cardiovascular Medicine, Nashville, TN (J-E.S., J.M.) – sequence: 3 givenname: Sebastian surname: Clauss fullname: Clauss, Sebastian organization: DZHK (German Centre for Cardiovascular Research), Partner Site Munich, Munich Heart Alliance, Germany (S.C.) – sequence: 4 givenname: Alan surname: Hanley fullname: Hanley, Alan organization: Cardiovascular Research Center (L.X., S.C., A.H., A.B., J.T., M.N., P.T.E., D.J.M.), Massachusetts General Hospital and Harvard Medical School, Boston, MA – sequence: 5 givenname: Aneesh surname: Bapat fullname: Bapat, Aneesh organization: Cardiovascular Research Center (L.X., S.C., A.H., A.B., J.T., M.N., P.T.E., D.J.M.), Massachusetts General Hospital and Harvard Medical School, Boston, MA – sequence: 6 givenname: Maarten surname: Hulsmans fullname: Hulsmans, Maarten organization: Center for Systems Biology, Department of Radiology (M.H., Y.I., G.W., M.J.S., M.N.), Massachusetts General Hospital and Harvard Medical School, Boston, MA – sequence: 7 givenname: Yoshiko surname: Iwamoto fullname: Iwamoto, Yoshiko organization: Center for Systems Biology, Department of Radiology (M.H., Y.I., G.W., M.J.S., M.N.), Massachusetts General Hospital and Harvard Medical School, Boston, MA – sequence: 8 givenname: Gregory surname: Wojtkiewicz fullname: Wojtkiewicz, Gregory organization: Center for Systems Biology, Department of Radiology (M.H., Y.I., G.W., M.J.S., M.N.), Massachusetts General Hospital and Harvard Medical School, Boston, MA – sequence: 9 givenname: Murat surname: Cetinbas fullname: Cetinbas, Murat organization: Department of Genetics, Harvard Medical School, Boston, MA (M.C.) – sequence: 10 givenname: Maximilian J surname: Schloss fullname: Schloss, Maximilian J organization: Center for Systems Biology, Department of Radiology (M.H., Y.I., G.W., M.J.S., M.N.), Massachusetts General Hospital and Harvard Medical School, Boston, MA – sequence: 11 givenname: Justin surname: Tedeschi fullname: Tedeschi, Justin organization: Cardiovascular Research Center (L.X., S.C., A.H., A.B., J.T., M.N., P.T.E., D.J.M.), Massachusetts General Hospital and Harvard Medical School, Boston, MA – sequence: 12 givenname: Bénédicte surname: Lebrun-Vignes fullname: Lebrun-Vignes, Bénédicte organization: Université Paris Est (UPEC), IRMB- EA 7379 EpiDermE (Epidemiology in Dermatology and Evaluation of Therapeutics), F-94010, Créteil, France (B.L-V.) – sequence: 13 givenname: Alicia surname: Lundby fullname: Lundby, Alicia organization: Department of Biomedical Sciences, Faculty of Health and Medical Sciences and NNF Center for Protein Research, Københavns Universitet, Copenhagen, Denmark (A.L.) – sequence: 14 givenname: Ruslan I surname: Sadreyev fullname: Sadreyev, Ruslan I organization: Department of Pathology (R.I.S.), Massachusetts General Hospital and Harvard Medical School, Boston, MA – sequence: 15 givenname: Javid surname: Moslehi fullname: Moslehi, Javid organization: Vanderbilt University Medical Center, Cardio-Oncology Program, Division of Cardiovascular Medicine, Nashville, TN (J-E.S., J.M.) – sequence: 16 givenname: Matthias surname: Nahrendorf fullname: Nahrendorf, Matthias organization: Center for Systems Biology, Department of Radiology (M.H., Y.I., G.W., M.J.S., M.N.), Massachusetts General Hospital and Harvard Medical School, Boston, MA – sequence: 17 givenname: Patrick T surname: Ellinor fullname: Ellinor, Patrick T organization: Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA (P.T.E.) – sequence: 18 givenname: David J surname: Milan fullname: Milan, David J organization: Leducq Foundation, Boston, MA (D.J.M.) |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33092403$$D View this record in MEDLINE/PubMed https://hal.sorbonne-universite.fr/hal-03099533$$DView record in HAL |
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Keywords | ibrutinib BTK protein, human atrial fibrillation electrophysiology protein kinase inhibitors CSK tyrosine-protein kinase |
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Snippet | Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF),... Background: Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial... BACKGROUNDIbrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial... Background:Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial... |
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SubjectTerms | Cardiology and cardiovascular system Human health and pathology Life Sciences Pharmaceutical sciences Pharmacology |
Title | Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase |
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