Mitochondrial Dysfunction Underlies the Integrated Stress Response Activation in Ponatinib-Induced Cardiotoxicity

线粒体功能障碍是帕纳替尼诱导的心脏毒性中综合应激反应激活的基础

• 批准号: 10735043
• 负责人: Won Hee Lee
• 金额: $ 54.72万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-18 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735043
• 关键词: Adenosine Triphosphate; Adult; Affect; Apoptotic; BCR gene; Binding; Cancer Burden; Cancer Patient; Cancer Prognosis; Cancer Survivor; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cardiovascular system; Cell Death; Cell Line; Cells; Chronic Myeloid Leukemia; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Complement; Complex; Coupled; Couples; Data; Defect; Distress; EIF-2alpha; Effectiveness; Event; FDA approved; Gatekeeping; Generations; Genes; Heart; Heart Injuries; Heart failure; Human; Impairment; In Vitro; Individual; Induction of Apoptosis; Injury; Intervention; K-562; Knock-out; Knowledge; Link; Maintenance; Malignant Neoplasms; Mediating; Mitochondria; Modeling; Molecular; Mus; Mutation; Myocardial dysfunction; Names; Oncology; Outcome; Oxidation-Reduction; Oxidative Stress; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Play; Prevalence; Protein Biosynthesis; Reactive Oxygen Species; Research Proposals; Resistance; Risk; Role; Signal Pathway; Signal Transduction; Stress; Study models; Therapeutic; Time; Toxic effect; Transgenic Organisms; Treatment Efficacy; Treatment-Related Cancer; Tyrosine Kinase Inhibitor; Up-Regulation; biological adaptation to stress; cancer cell; cardioprotection; cell type; chronic myeloid leukemia cell; clinically relevant; extracellular; improved; in vivo; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; inhibitor; innovation; insight; knockout gene; mitochondrial dysfunction; molecular targeted therapies; mortality; mouse model; neoplastic cell; novel; overexpression; patient prognosis; pharmacologic; protective effect; proteostasis; small molecule; success; systemic toxicity; therapeutic target; tool; tumor; tumor progression

PROJECT SUMMARY There has been a significant decline in cancer related mortality, partly due to the emergence of molecular targeted therapies. Unfortunately, the success of these drugs including tyrosine kinase inhibitors (TKIs) has been tempered by a concomitant rise in the prevalence of cancer therapies-related cardiotoxicity. Ponatinib, a currently FDA-approved third-generation TKI, is used to treat chronic myeloid leukemia (CML) patients carrying the gatekeeper mutation breakpoint cluster region-Abelson (BCR-ABL) T315I. Despite its effectiveness, a considerable number of patients receiving ponatinib suffers from various cardiac complications. Several studies have linked ponatinib-induced cardiotoxicity to impaired pro-survival signaling pathways leading to cell death. However, the molecular signaling pathways leading to these events remain obscure and a better understanding of how cardiomyocytes respond to ponatinib may provide new insights into novel mitigation therapies. The heart must adapt to stress conditions that occur as a result of intracellular or extracellular factors. The integrated stress response (ISR) is one of the circuits responding to stress and serving to restore proteostasis by regulating protein synthesis, although prolonged ISR activation leads to cell death. Whether the ISR is activated and plays a protective or detrimental role in ponatinib-induced cardiotoxicity are largely unknown and may represent an amenable therapeutic target which will be the focus of my current proposal. My preliminary data suggests that ponatinib causes mitochondrial dysfunction in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Interestingly, mitochondrial damage appears to trigger activation of the ISR and is mediated by a kinase called general control non-repressed 2 (GCN2). I also found that inhibition of the ISR using a novel small molecule called ISR inhibitor (ISRIB) successfully blunted the cardiotoxic effects of ponatinib both in vitro and in vivo. Hence, the central hypothesis of my proposal is that the ISR pathway which is activated upon sensing mitochondrial damage plays a pivotal role in mediating ponatinib-induced cardiotoxicity. Aim 1 will investigate whether activation of GCN2 couples mitochondrial damage to ISR activation upon impaired mitochondrial reactive oxygen species (ROS) and adenosine triphosphate (ATP) level. Aim 2 will assess whether ponatinib induces apoptosis and cardiac dysfunction through the GCN2/eIF2α/ATF4 axis. Lastly, aim 3 will explore whether pharmacological suppression of the ISR even after the onset of ponatinib-induced cardiotoxicity remains cardioprotective without compromising the efficacy of ponatinib against tumor cells. Taken together, at the conclusion of these studies, we will have significantly expanded our knowledge by which how ponatinib-induced mitochondrial dysfunction is sensed to trigger the ISR; whether this activation contributes to cardiac pathology; and if crosstalk between these two pathways can be targeted as a therapeutic avenue to mitigate ponatinib- induced cardiotoxicity clinically.

项目总结 与癌症相关的死亡率显著下降，部分原因是分子的出现。 有针对性的治疗。不幸的是，包括酪氨酸激酶抑制剂(TKIs)在内的这些药物的成功 随着癌症治疗相关心脏毒性流行率的上升而有所缓和。波纳替尼，目前的 FDA批准的第三代TKI，用于治疗携带 关守突变断点簇区-Abelson(BCR-ABL)T315I。尽管它很有效，但一个 接受波纳替尼治疗的患者中，有相当数量的患者患有各种心脏并发症。几项研究 已将波纳替尼诱导的心脏毒性与受损的促生存信号通路联系起来，从而导致细胞死亡。 然而，导致这些事件的分子信号通路仍然不清楚，而且人们对此有更好的理解 心肌细胞对波纳替尼的反应可能为新的缓解疗法提供新的见解。心脏 必须适应细胞内或细胞外因素造成的压力条件。综合压力 应答(ISR)是对应激作出反应并通过调节蛋白质来恢复蛋白平衡的回路之一 合成，尽管长时间的ISR激活会导致细胞死亡。ISR是否被激活并播放 在波纳替尼诱导的心脏毒性中的保护或有害作用在很大程度上是未知的，可能代表着一种 顺从的治疗目标，这将是我目前提议的重点。我的初步数据显示 波那替尼引起人诱导的多能干细胞来源的心肌细胞线粒体功能障碍 (HiPSC-CMS)。有趣的是，线粒体损伤似乎触发了ISR的激活，并通过一种 被称为一般对照非抑制因子2(GCN2)的激酶。我还发现，抑制ISR使用的是一种新颖的小 一种名为ISR抑制剂(ISRIB)的分子在体外和体内成功地钝化了波纳替尼的心脏毒性作用 活着。因此，我的建议的中心假设是，在感知时激活的ISR通路 线粒体损伤在介导波纳替尼诱导的心脏毒性中起着关键作用。AIM 1将调查 GCN2的激活是否将线粒体损伤与受损线粒体的ISR激活结合起来 活性氧(ROS)和三磷酸腺苷(ATP)水平。目标2将评估波纳替尼 通过GCN2/eIF2α/ATF4轴诱导细胞凋亡和心功能障碍。最后，《目标3》将探讨 即使在帕纳替尼诱导的心脏毒性开始后，ISR的药理抑制仍然存在 在不影响波纳替尼抗肿瘤细胞疗效的情况下保护心脏。放在一起，在 这些研究的结论，我们将大大扩展我们的知识，通过这些知识，波纳替尼是如何诱导 线粒体功能障碍被感知为触发ISR；这种激活是否有助于心脏病理； 如果这两条通路之间的串扰可以作为一种治疗途径来缓解帕纳替尼- 临床上出现心脏毒性。