{"id":12167,"date":"2023-07-28T14:12:30","date_gmt":"2023-07-28T14:12:30","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&p=12167"},"modified":"2024-01-10T22:14:07","modified_gmt":"2024-01-10T22:14:07","slug":"2023-po-01-173-ibrutinib-treatment-results-in-increased-phosphorylation-of-the-erk1-2-signaling-pathway-in-atrial-specific-human-ipsc-derived-cardiomyocytes","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2023-po-01-173-ibrutinib-treatment-results-in-increased-phosphorylation-of-the-erk1-2-signaling-pathway-in-atrial-specific-human-ipsc-derived-cardiomyocytes\/","title":{"rendered":"2023 – PO-01-173 Ibrutinib treatment results in increased phosphorylation of the ERK1\/2 signaling pathway in atrial-specific human iPSC-derived cardiomyocytes"},"content":{"rendered":"
\n

Background<\/span><\/strong><\/p>\n

Cardiovascular sequelae of targeted cancer therapies may provide novel insights into cardiovascular biology and disease pathogenesis, including atrial fibrillation (AF). The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has revolutionized treatment for B-cell malignancies but increases the incidence of AF compared with conventional chemotherapy. Recent data in mouse models have shown that ibrutinib mediated-AF likely results not from inhibition of BTK (\u201con target\u201d effect), but from off-target inhibition of a different kinase, C-terminal Src kinase (CSK). The signaling pathway by which CSK inhibition results in AF remains unknown and thus may represent a novel mechanism for AF molecular pathogenesis.<\/div>\n<\/section>\n
\n

Objective<\/span><\/strong><\/p>\n

To test the hypothesis that ibrutinib generates atrial fibrillation in susceptible patients by targeting signaling pathways downstream from CSK.<\/div>\n<\/section>\n
\n

Methods<\/span><\/strong><\/p>\n

We studied cellular monolayers of hiPSC-aCMs using extracellular field potential (EFP) recordings obtained by the Nanion CardioExcyte 96 system after 72-hour exposure to ibrutinib, the second-generation BTK inhibitor acalabrutinib, or vehicle. As an initial proteomic approach to determining which kinase signaling pathways are altered upon inhibition of CSK and hence may predispose to AF arrhythmogenesis, we used a human phospho-antibody array to study the relative phosphorylation state of 37 kinases in hiPSC-aCMs treated with ibrutinib or vehicle.<\/div>\n<\/section>\n
\n

Results<\/span><\/strong><\/p>\n

EFP recordings from cellular monolayers of hiPSC-aCMs exposed to ibrutinib for 24 hours develop a striking increase in spontaneous beat-to-beat variability, an\u00a0in vitro<\/em>\u00a0correlate of arrhythmogenic behavior. This effect was not seen with vehicle control or the second-generation BTK inhibitor acalabrutinib, which is less arrhythmogenic in clinical trials. Treatment with ibrutinib for 72 hours resulted in increased phosphorylation of multiple kinases in the Erk1\/2 pathway, including Erk1 T202\/Y204 and Erk2 T185\/Y187, in human phospho-kinase array studies. Traditional Western Blotting confirmed these results and showed that ibrutinib, but not acalabrutinib, resulted in increased Erk1\/2 phosphorylation.<\/div>\n<\/section>\n
\n

Conclusion<\/span><\/strong><\/p>\n

Off-target inhibition of CSK by ibrutinib may result in increased AF through the ERK1\/2 pathway, consistent with previous reports implicating increased phosphorylation in the ERK1\/2 pathway in the pathogenesis of AF. The downstream mechanisms by which this occurs remain unknown and thus represents a novel potential target for AF therapeutics.<\/div>\n<\/section>\n
<\/div>\n
Read more in the publication here<\/a>.<\/div>\n","protected":false},"featured_media":0,"template":"","products_tags":[34],"resource_type":[75],"application_areas":[53,77],"therapeutic_areas":[54,143],"target_categories":[],"target_families":[],"targets":[],"resource_keyword":[],"class_list":["post-12167","resource_library","type-resource_library","status-publish","hentry","products_tags-cardioexcyte-96","resource_type-publication","application_areas-assay-development-and-validation","application_areas-cell-ipscs-profiling","therapeutic_areas-cardiac-safety-cipa","therapeutic_areas-assay-development-and-validation"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/12167","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/media?parent=12167"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=12167"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=12167"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=12167"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=12167"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=12167"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=12167"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=12167"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=12167"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}