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.

项目概要 癌症相关死亡率显着下降，部分原因是分子生物学的出现 靶向治疗。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一直被忽视。 与癌症治疗相关的心脏毒性的患病率随之上升，从而缓和了这一趋势。帕纳替尼，目前 FDA批准的第三代TKI，用于治疗携带该基因的慢性粒细胞白血病（CML）患者 看门人突变断点簇区域-Abelson (BCR-ABL) T315I。尽管其有效性， 相当多接受普纳替尼治疗的患者患有各种心脏并发症。多项研究 已将普纳替尼诱导的心脏毒性与导致细胞死亡的促生存信号通路受损联系起来。 然而，导致这些事件的分子信号传导途径仍然模糊，需要更好的理解 心肌细胞如何响应普纳替尼可能为新型缓解疗法提供新的见解。心脏 必须适应由于细胞内或细胞外因素而发生的应激条件。综合应力 反应（ISR）是对压力作出反应的回路之一，通过调节蛋白质来恢复蛋白质稳态 合成，尽管延长 ISR 激活会导致细胞死亡。 ISR是否激活并播放 在 ponatinib 诱导的心脏毒性中的保护或有害作用在很大程度上尚不清楚，可能代表 合理的治疗目标将是我当前建议的重点。我的初步数据表明 ponatinib 导致人诱导多能干细胞来源的心肌细胞线粒体功能障碍 （hiPSC-CM）。有趣的是，线粒体损伤似乎会触发 ISR 的激活，并由 激酶称为一般控制非抑制 2 (GCN2)。我还发现使用一种新型的小分子药物可以抑制 ISR 称为 ISR 抑制剂 (ISRIB) 的分子在体外和体内成功地减弱了 ponatinib 的心脏毒性作用 体内。因此，我的建议的中心假设是，ISR 通路在感知时被激活 线粒体损伤在介导普纳替尼诱导的心脏毒性中起着关键作用。目标 1 将进行调查 GCN2 的激活是否将线粒体损伤与线粒体受损时的 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 ponatinib 是否 通过 GCN2/eIF2α/ATF4 轴诱导细胞凋亡和心脏功能障碍。最后，目标 3 将探讨是否 即使在 ponatinib 诱导的心脏毒性发生后，ISR 的药物抑制仍然存在 具有心脏保护作用，且不影响普纳替尼对抗肿瘤细胞的功效。综合起来，在 这些研究的结论，我们将显着扩展我们的知识，通过这些研究，ponatinib如何诱导 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学； 如果这两种途径之间的串扰可以作为减轻 ponatinib 的治疗途径 临床上可引起心脏毒性。