Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
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 tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
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