Xin Li MD , Song Lin MD , Jiayi Huang MD , Yongping Lin PhD , Zhongbao Ruan MD, FACC
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引用次数: 0
Abstract
Background
Compared with earlier generations of epidermal growth factor receptor–tyrosine kinase inhibitors, the third-generation agent osimertinib demonstrates superior efficacy in patients with non–small cell lung cancer and has become the first-line treatment, but is associated with more pronounced cardiotoxicity, especially arrhythmia.
Objective
This study aimed to investigate the underlying mechanisms of the potential proarrhythmic effects of osimertinib.
Methods
We investigated osimertinib’s effects on cell viability, structure, and electrophysiological properties of human induced pluripotent stem cell–derived cardiomyocytes using cell viability assays, immunofluorescence staining, transmission electron microscopy, and optical mapping. A zebrafish in vivo model was used to validate cardiotoxicity. Western blotting (WB) assessed relative protein expression on cardiomyocyte membranes, whereas RNA sequencing and quantitative reverse transcription polymerase chain reaction identified significantly altered signaling pathways and target genes. Rescue experiments were conducted to confirm the pathogenic mechanism.
Results
The cell viability assay indicated that osimertinib reduced human induced pluripotent stem cell–derived cardiomyocyte viability (half-maximal inhibitory concentration = 3.492 μM). At this osimertinib concentration, immunofluorescence revealed disorganized myofilament sarcomeres, and transmission electron microscopy showed increased mitochondrial damage, whereas optical mapping demonstrated prolonged action potential duration and elevated incidence of early afterdepolarizations even at a near-physiological concentration. In vivo studies demonstrated that osimertinib-exposed zebrafish exhibited bradycardia, pericardial edema, and prolonged QT interval. WB revealed no significant changes in the expression of epidermal growth factor receptor. RNA sequencing revealed significant downregulation of potassium ion channel genes, with quantitative reverse transcription polymerase chain reaction and WB analysis demonstrating the most pronounced decrease in potassium calcium-activated channel subfamily N member 1 (KCNN1) expression. Modulating KCNN1 expression can reverse the electrophysiological alterations.
Conclusion
Osimertinib prolongs action potential duration and promotes arrhythmias through off-target inhibition of KCNN1 expression.
期刊介绍:
HeartRhythm, the official Journal of the Heart Rhythm Society and the Cardiac Electrophysiology Society, is a unique journal for fundamental discovery and clinical applicability.
HeartRhythm integrates the entire cardiac electrophysiology (EP) community from basic and clinical academic researchers, private practitioners, engineers, allied professionals, industry, and trainees, all of whom are vital and interdependent members of our EP community.
The Heart Rhythm Society is the international leader in science, education, and advocacy for cardiac arrhythmia professionals and patients, and the primary information resource on heart rhythm disorders. Its mission is to improve the care of patients by promoting research, education, and optimal health care policies and standards.