Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase

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Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase. / 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; Moslehi, Javid; Nahrendorf, Matthias; Ellinor, Patrick T.; Milan, David J.

I: Circulation, Bind 142, Nr. 25, 2020, s. 2443-2455.

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

Harvard

Xiao, L, Salem, J-E, Clauss, S, Hanley, A, Bapat, A, Hulsmans, M, Iwamoto, Y, Wojtkiewicz, G, Cetinbas, M, Schloss, MJ, Tedeschi, J, Lebrun-Vignes, B, Lundby, A, Sadreyev, R, Moslehi, J, Nahrendorf, M, Ellinor, PT & Milan, DJ 2020, 'Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase', Circulation, bind 142, nr. 25, s. 2443-2455. https://doi.org/10.1161/CIRCULATIONAHA.120.049210

APA

Xiao, L., Salem, J-E., Clauss, S., Hanley, A., Bapat, A., Hulsmans, M., Iwamoto, Y., Wojtkiewicz, G., Cetinbas, M., Schloss, M. J., Tedeschi, J., Lebrun-Vignes, B., Lundby, A., Sadreyev, R., Moslehi, J., Nahrendorf, M., Ellinor, P. T., & Milan, D. J. (2020). Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase. Circulation, 142(25), 2443-2455. https://doi.org/10.1161/CIRCULATIONAHA.120.049210

Vancouver

Xiao L, Salem J-E, Clauss S, Hanley A, Bapat A, Hulsmans M o.a. Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase. Circulation. 2020;142(25):2443-2455. https://doi.org/10.1161/CIRCULATIONAHA.120.049210

Author

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 ; Moslehi, Javid ; Nahrendorf, Matthias ; Ellinor, Patrick T. ; Milan, David J. / Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase. I: Circulation. 2020 ; Bind 142, Nr. 25. s. 2443-2455.

Bibtex

@article{1a7d2b63a15d4924a7fa39d5256b2077,
title = "Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase",
abstract = "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; PCONCLUSIONS: These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF.REGISTRATION: URL: https://ww.clinicaltrials.gov; Unique identifier: NCT03530215.",
keywords = "atrial fibrillation, BTK protein, human, CSK tyrosine-protein kinase, electrophysiology, ibrutinib, protein kinase inhibitors, TYROSINE-KINASE, FAMILY KINASES, INFLAMMATION, RISK, GENE, PHARMACOKINETICS, ACALABRUTINIB, MULTICENTER, ARRHYTHMIAS, ACTIVATION",
author = "Ling Xiao and Joe-Elie Salem and Sebastian Clauss and Alan Hanley and Aneesh Bapat and Maarten Hulsmans and Yoshiko Iwamoto and Gregory Wojtkiewicz and Murat Cetinbas and Schloss, {Maximilian J.} and Justin Tedeschi and Benedicte Lebrun-Vignes and Alicia Lundby and Ruslan Sadreyev and Javid Moslehi and Matthias Nahrendorf and Ellinor, {Patrick T.} and Milan, {David J.}",
year = "2020",
doi = "10.1161/CIRCULATIONAHA.120.049210",
language = "English",
volume = "142",
pages = "2443--2455",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams & Wilkins",
number = "25",

}

RIS

TY - JOUR

T1 - Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase

AU - Xiao, Ling

AU - Salem, Joe-Elie

AU - Clauss, Sebastian

AU - Hanley, Alan

AU - Bapat, Aneesh

AU - Hulsmans, Maarten

AU - Iwamoto, Yoshiko

AU - Wojtkiewicz, Gregory

AU - Cetinbas, Murat

AU - Schloss, Maximilian J.

AU - Tedeschi, Justin

AU - Lebrun-Vignes, Benedicte

AU - Lundby, Alicia

AU - Sadreyev, Ruslan

AU - Moslehi, Javid

AU - Nahrendorf, Matthias

AU - Ellinor, Patrick T.

AU - Milan, David J.

PY - 2020

Y1 - 2020

N2 - 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; PCONCLUSIONS: These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF.REGISTRATION: URL: https://ww.clinicaltrials.gov; Unique identifier: NCT03530215.

AB - 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; PCONCLUSIONS: These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF.REGISTRATION: URL: https://ww.clinicaltrials.gov; Unique identifier: NCT03530215.

KW - atrial fibrillation

KW - BTK protein, human

KW - CSK tyrosine-protein kinase

KW - electrophysiology

KW - ibrutinib

KW - protein kinase inhibitors

KW - TYROSINE-KINASE

KW - FAMILY KINASES

KW - INFLAMMATION

KW - RISK

KW - GENE

KW - PHARMACOKINETICS

KW - ACALABRUTINIB

KW - MULTICENTER

KW - ARRHYTHMIAS

KW - ACTIVATION

U2 - 10.1161/CIRCULATIONAHA.120.049210

DO - 10.1161/CIRCULATIONAHA.120.049210

M3 - Journal article

C2 - 33092403

VL - 142

SP - 2443

EP - 2455

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 25

ER -

ID: 255212490