Abstract 4139038: Ibrutinib Increases Phosphorylation of the Src-Erk1/2 Signaling Pathway in Human Atrial-Specific Cardiomyocytes Derived from Induced Pluripotent Stem Cells

医学 伊布替尼 磷酸化 诱导多能干细胞 信号转导 细胞生物学 干细胞 原癌基因酪氨酸蛋白激酶Src 癌症研究 受体 内科学 生物化学 白血病 胚胎干细胞 生物 慢性淋巴细胞白血病 基因
作者
Matthew R. Fleming,Matthew J. O’Neill,Tao Yang,Joseph F. Solus,Brett M. Kroncke,Björn C. Knollmann,Javid J. Moslehi,Dan M. Roden
出处
期刊:Circulation [Lippincott Williams & Wilkins]
卷期号:150 (Suppl_1)
标识
DOI:10.1161/circ.150.suppl_1.4139038
摘要

Background: The Bruton’s 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. Objective: To identify kinase pathways that promote atrial fibrillation downstream from CSK. Methods: Studies 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. Results: Treatment 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). Conclusion: In 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.

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