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.

项目摘要 癌症相关的死亡率显着下降，部分原因是分子的出现 靶向疗法。不幸的是，包括酪氨酸激酶抑制剂（TKI）在内的这些药物的成功已经 随着癌症疗法相关性心脏毒性的患病率的伴随增长。 Ponatinib，目前 FDA批准的第三代TKI用于治疗携带慢性髓样白血病（CML）患者 网守突变断裂点群集区域 - 阿伯森（BCR-ABL）T315i。尽管它有效，但 大量接受Ponatinib的患者患有各种心脏并发症。几项研究 已经将ponatinib诱导的心脏毒性与导致细胞死亡的促生物氧气传导途径相关联。 但是，导致这些事件的分子信号传导途径仍然晦涩难懂，并且更好地理解 心肌细胞如何对Ponatinib反应可能会为新型缓解疗法提供新的见解。心 必须适应由于细胞内或细胞外因子而发生的应力条件。综合应力 反应（ISR）是通过调节蛋白质来响应压力和恢复蛋白质的电路之一 尽管延长ISR激活导致细胞死亡，但合成。 ISR是否被激活并播放 在Ponatinib诱导的心脏毒性中的保护性或有害作用在很大程度上未知，可能代表 正式的治疗靶标，这将是我当前建议的重点。我的初步数据表明 Ponatinib在人诱导的多能干细胞衍生的心肌细胞中引起线粒体功能障碍 （HIPSC-CMS）。有趣的是，线粒体损伤似乎触发了ISR的激活，并由A介导 激酶称为通用对照非抑制2（GCN2）。我还发现使用新颖的小型ISR抑制ISR 称为ISR抑制剂（ISRIB）的分子成功地使Ponatinib的心脏毒性在体外和IN中均为 体内。因此，我的提议的中心假设是在感应时激活的ISR途径 线粒体损伤在介导Ponatinib诱导的心脏毒性中起关键作用。 AIM 1将调查 在线粒体受损时，GCN2夫妇的激活是否激活ISR激活 活性氧（ROS）和三磷酸腺苷（ATP）水平。 AIM 2将评估Ponatinib是否 通过GCN2/EIF2α/ATF4轴诱导凋亡和心脏功能障碍。最后，AIM 3将探讨是否 即使在Ponatinib诱导的心脏毒性发作后，ISR的药理抑制也会抑制 心脏保护性，而不会损害Ponatinib对肿瘤细胞的效率。一起，在 结论这些研究，我们将大大扩展我们的知识 线粒体功能障碍被感知以触发ISR。这种激活是否有助于心脏病理； 如果这两种途径之间的串扰可以作为一种治疗途径，以减轻Ponatinib- 临床诱导心脏毒性。