{"id":16547,"date":"2024-12-02T08:16:42","date_gmt":"2024-12-02T08:16:42","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=16547"},"modified":"2024-12-02T08:16:42","modified_gmt":"2024-12-02T08:16:42","slug":"2024-ibrutinib-increases-phosphorylation-of-the-src-erk1-2-signaling-pathway-in-human-atrial-specific-cardiomyocytes-derived-from-induced-pluripotent-stem-cells","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2024-ibrutinib-increases-phosphorylation-of-the-src-erk1-2-signaling-pathway-in-human-atrial-specific-cardiomyocytes-derived-from-induced-pluripotent-stem-cells\/","title":{"rendered":"2024 &#8211; Ibrutinib Increases Phosphorylation of the Src-Erk1\/2 Signaling Pathway in Human Atrial-Specific Cardiomyocytes Derived from Induced Pluripotent Stem Cells"},"content":{"rendered":"<div role=\"paragraph\"><strong>Background:<\/strong>\u00a0The Bruton\u2019s tyrosine kinase (BTK) inhibitor ibrutinib has revolutionized treatment for B-cell malignancies but increases the incidence of atrial fibrillation (AF) compared with conventional chemotherapy. Reports indicate that ibrutinib-mediated AF does not result from inhibition of BTK, but from off-target inhibition of a different kinase, C-terminal Src kinase (CSK). The signaling pathway by which CSK inhibition results in AF is unknown and may represent a novel molecular mechanism for AF.<\/div>\n<div role=\"paragraph\"><b>Objective:<\/b>\u00a0To identify kinase pathways that promote atrial fibrillation downstream from CSK.<\/div>\n<div role=\"paragraph\"><b>Methods:<\/b>\u00a0Studies were performed in human atrial-specific cardiomyocytes (hiPSC-aCMs) derived from population control induced pluripotent stem cells. Extracellular field potentials (EFPs) with the Nanion CardioExcyte 96 system demonstrated marked increased spontaneous beat-to-beat variability, an in vitro correlate of arrhythmogenic behavior, with exposure to ibrutinib but not to second-generation BTK inhibitors, which are less associated with AF (Figure 1A). Human phospho-kinase arrays determined the relative phosphorylation of 37 kinases in hiPSC-aCMs treated with ibrutinib or vehicle.<\/div>\n<div role=\"paragraph\"><b>Results:<\/b>\u00a0Treatment with ibrutinib increased phosphorylation of multiple kinases (Src, Erk1\/2, CREB) in the Src-Erk1\/2 pathway (Figure 2); the biggest increase was with Erk1\/2 phosphorylation (3-fold). Pre-treatment of hiPSC-aCMs with the Erk1\/2 inhibitors ulixertinib and SCH772984 inhibited the EFP arrhythmogenic signal seen with ibrutinib (Figure 1B).<\/div>\n<div role=\"paragraph\"><b>Conclusion:<\/b>\u00a0In hiPSC-aCMs, inhibition of CSK by ibrutinib results in increased arrhythmogenic behavior through Erk1\/2-dependent phosphorylation. The downstream mechanisms by which this occurs remain unknown and represent novel potential target(s) for AF therapeutics.<\/div>\n","protected":false},"featured_media":0,"template":"","products_tags":[34],"resource_type":[75],"application_areas":[53,76,77],"therapeutic_areas":[143],"target_categories":[],"target_families":[],"targets":[],"resource_keyword":[],"class_list":["post-16547","resource_library","type-resource_library","status-publish","hentry","products_tags-cardioexcyte-96","resource_type-publication","application_areas-assay-development-and-validation","application_areas-drug-discovery","application_areas-cell-ipscs-profiling","therapeutic_areas-assay-development-and-validation"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/16547","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=16547"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=16547"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=16547"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=16547"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=16547"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=16547"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=16547"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=16547"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=16547"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}