Ibrutinib therapy results in atrial fibrillation through modulation of the Src-Erk1/2 pathway

Abstract

The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has revolutionized treatment for B-cell malignancies but increases the incidence of atrial fibrillation (AF) compared to conventional chemotherapy. The downstream signaling pathways through which ibrutinib leads to AF are unknown and may represent a novel molecular mechanism for AF. To identify kinase signaling pathways that promote atrial fibrillation during ibrutinib therapy. Studies were performed in human atrial-specific cardiomyocytes derived from population control induced pluripotent stem cells (hiPSC-aCMs). Electrophysiologic measurements, including extracellular field potentials (EFPs), were conducted with the Nanion CardioExcyte96 system. Human phospho-kinase arrays determined the relative phosphorylation of 37 kinases in hiPSC-aCMs treated with either ibrutinib or vehicle control. Extracellular field potentials demonstrated a marked increase in spontaneous beat-to-beat variability, an in vitro correlate of arrhythmogenic behavior, with exposure to ibrutinib but not to second or third-generation BTK inhibitors, which are less associated with AF. Treatment with ibrutinib increased phosphorylation of multiple kinases (Src, Erk1/2, CREB) in the Src-Erk1/2 pathway; the most significant increase was with Erk1/2 phosphorylation (threefold). Pre-treatment of hiPSC-aCMs with the Erk1/2 inhibitors ulixertinib and SCH772984 inhibited the EFP arrhythmogenic signal seen with ibrutinib. In hiPSC-aCMs, ibrutinib treatment leads to increased arrhythmogenic behavior via the Src-Erk1/2 phosphorylation pathway. The inhibition of Erk1/2 or its downstream targets may represent novel pathways in the development of atrial fibrillation, providing new targets for therapeutic development.