Human-Induced Pluripotent Stem Cell Model of Trastuzumab-Induced Cardiac Dysfunction in Patients With Breast Cancer
Human-Induced Pluripotent Stem Cell Model of Trastuzumab-Induced Cardiac Dysfunction in Patients With Breast Cancer
复制标题
曲妥珠单抗诱导乳腺癌患者心功能障碍的人诱导多能干细胞模型
DOI：
10.1161/circulationaha.118.037357
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发表时间：
2019-05-21
期刊：
影响因子：
37.8
通讯作者：
Wu, Joseph C.
中科院分区：
文献类型：
--
作者：
Kitani, Tomoya;Ong, Sang-Ging;Wu, Joseph C.
背景：分子靶向化疗已被证明可以显著改善癌症患者的预后，但它们经常引起心血管副作用，限制了它们的使用并损害了患者的生活质量。与传统化疗引起的心脏毒性相比，这些疗法（尤其是曲妥珠单抗）诱导的心功能障碍显示出独特的心脏毒性临床表型。方法：我们使用人诱导多能干细胞衍生心肌细胞（iPSC-CM）平台来确定曲妥珠单抗诱导心功能障碍的潜在细胞机制。我们评估了曲妥珠单抗对健康个体iPSC-CMs结构和功能特性的影响，并进行了rna测序以进一步研究曲妥珠单抗对iPSC-CMs的影响。我们还从接受曲妥珠单抗治疗的患者身上产生了人诱导多能干细胞，并检查了患者的表型是否可以通过患者特异性iPSC-CMs在体外重现。结果：我们发现临床相关剂量的曲妥珠单抗显著损害iPSC-CMs的收缩和钙处理特性，而不诱导心肌细胞死亡或肌体紊乱。rna测序和随后的功能分析显示，线粒体功能障碍和心脏能量代谢途径的改变是曲妥珠单抗诱导的心脏毒性表型的主要原因。接受曲妥珠单抗治疗并经历严重心功能障碍的患者产生的人类iPSC-CMs比曲妥珠单抗治疗后未经历心功能障碍的患者产生的iPSC-CMs更容易受到曲妥珠单抗治疗的影响。值得注意的是，使用amp激活的蛋白激酶激活剂进行代谢调节可以避免曲妥珠单抗诱导的不良反应。结论：我们的研究结果表明，心肌细胞代谢途径的改变可能是曲妥珠单抗治疗后心功能障碍发展的关键机制；因此，靶向代谢改变可能是曲妥珠单抗诱导心功能障碍的一种有希望的治疗方法。
Background: Molecular targeted chemotherapies have been shown to significantly improve the outcomes of patients who have cancer, but they often cause cardiovascular side effects that limit their use and impair patients' quality of life. Cardiac dysfunction induced by these therapies, especially trastuzumab, shows a distinct cardiotoxic clinical phenotype in comparison to the cardiotoxicity induced by conventional chemotherapies.Methods: We used the human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) platform to determine the underlying cellular mechanisms in trastuzumab-induced cardiac dysfunction. We assessed the effects of trastuzumab on structural and functional properties in iPSC-CMs from healthy individuals and performed RNA-sequencing to further examine the effect of trastuzumab on iPSC-CMs. We also generated human induced pluripotent stem cells from patients receiving trastuzumab and examined whether patients' phenotype could be recapitulated in vitro by using patient-specific iPSC-CMs.Results: We found that clinically relevant doses of trastuzumab significantly impaired the contractile and calcium-handling properties of iPSC-CMs without inducing cardiomyocyte death or sarcomeric disorganization. RNA-sequencing and subsequent functional analysis revealed mitochondrial dysfunction and altered the cardiac energy metabolism pathway as primary causes of trastuzumab-induced cardiotoxic phenotype. Human iPSC-CMs generated from patients who received trastuzumab and experienced severe cardiac dysfunction were more vulnerable to trastuzumab treatment than iPSC-CMs generated from patients who did not experience cardiac dysfunction following trastuzumab therapy. It is important to note that metabolic modulation with AMP-activated protein kinase activators could avert the adverse effects induced by trastuzumab.Conclusions: Our results indicate that alterations in cellular metabolic pathways in cardiomyocytes could be a key mechanism underlying the development of cardiac dysfunction following trastuzumab therapy; therefore, targeting the altered metabolism may be a promising therapeutic approach for trastuzumab-induced cardiac dysfunction.