Defining the role of mitochondrial injury in MEK inhibitor cardiotoxicity

确定线粒体损伤在 MEK 抑制剂心脏毒性中的作用

• 批准号: 10753009
• 负责人: Brian C Jensen
• 金额: $ 53.36万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-11 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753009
• 关键词: Adverse effects; Allosteric Regulation; BRAF gene; Bioenergetics; Biology; Breast Cancer Cell; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cessation of life; Clinical Trials; Combined Modality Therapy; Common Neoplasm; Complex; Coupled; Data; Electron Transport; Etiology; Extracellular Signal Regulated Kinases; FDA approved; Functional disorder; Future; Genetic; Heart; Heart Injuries; Heart Mitochondria; Heart failure; Human; Immune; Immune checkpoint inhibitor; Immune response; Impairment; In Vitro; Inflammation; Inflammatory; Injury; Innate Immune Response; Life; MAP2K1 gene; MAPK3 gene; MEK inhibition; MEKs; Malignant Neoplasms; Mediating; Mitochondria; Molecular; Mus; Muscle Fibers; Myocardial; Oxidative Phosphorylation; Oxidative Stress; Oxidative Stress Induction; Pathway interactions; Patients; Pattern; Pattern recognition receptor; Permeability; Phase; Phenotype; Phosphorylation; Physiology; Process; Publishing; Ras/Raf; Reaction; Regulation; Research Personnel; Risk; Role; STAT3 gene; Testing; Therapeutic; Toxic effect; Transcript; Work; anti-cancer; cancer cell; cancer therapy; cardiovascular effects; clinically relevant; combination cancer therapy; complex IV; cytokine; diagnostic platform; experimental study; genetic manipulation; immune activation; in vivo; inhibitor; injured; innate immune pathways; melanoma; mouse model; novel; pharmacologic; pre-clinical; programmed cell death ligand 1; respiratory; targeted cancer therapy; targeted treatment; transcriptome sequencing; transcriptomics; triple-negative invasive breast carcinoma; tumor; tumorigenesis

PROJECT SUMMARY/ABSTRACT Persistent hyperactivation of the Ras-Raf-MEK-ERK pathway contributes to oncogenesis in over 30% of human cancers. Trametinib (Trm) is a highly selective inhibitor of MEK1, the sole upstream activator of multifunctional pro-survival kinases ERK1/2. Trm commonly is used in combination with dabrafenib to prolong life in patients with melanoma; its efficacy in other common tumor types including triple negative breast cancer (TNBC) is being widely explored. Trm generally is well tolerated, though it can cause cardiomyopathy that may lead to heart failure (HF) in up to 11% of cases. The mechanisms underlying Trm-associated cardiotoxicity are unclear. Our preliminary data show that 14-day Trm treatment abrogated mouse myocardial ERK1/2 activation and induced reversible cardiac contractile dysfunction characterized by reduced mitochondrial abundance and compromised oxidative phosphorylation in vivo. RNAseq analysis of Trm-treated mouse hearts revealed broad decreases in mitochondrial transcripts and increases in immune response pathways that are molecularly distinct from other HF etiologies. In vitro exposure of primary cardiomyocytes to Trm caused mitochondrial injury and activated canonical inflammatory pathways. These surprising effects were not predicted by our current understanding of MEK-ERK cardiomyocyte biology or by our understanding of the anticancer mechanisms of MEK inhibitors (MEKi’s). Here we will use 3 specific aims to test the central hypothesis that MEK-ERK inhibition impairs OXPHOS to induce mitochondrial injury resulting in innate immune activation, and that these effects collectively contribute to both the cardiotoxicity and anticancer efficacy of Trm. In the mechanistic Aim 1 we will find if Trm induces mitochondrial injury by compromising oxidative phosphorylation and inducing oxidative stress. Aim 2 will determine whether genetic or pharmacological loss of MEK function is sufficient to induce cardiomyocyte mitochondrial injury using novel mouse models of cardiomyocyte MEK1 deficiency and other FDA-approved pharmacological MEKi’s. Aim 3 will test whether Trm-induced mitochondrial toxicity activates innate immune responses in cardiomyocytes and cancer cells using a validated mouse model of TNBC and a clinically relevant combination targeted therapy. These studies will establish whether activation of pattern recognition receptors by mitochondrial damage associated molecular patterns contributes to Trm cardiotoxicity or anticancer efficacy, and will define whether the addition of Trm to an immune checkpoint inhibitor enhances cardiotoxic risk. The proposed experiments have the potential to impact the fields of myocardial biology and cancer therapeutics in related but distinct ways: (1) Expand our understanding of MEK-ERK regulation of cardiomyocyte mitochondrial function; (2) Identify the molecular processes that contribute to Trm cardiotoxicity; (3) Determine whether mitochondrial toxicity and innate immune activation contribute to the anticancer efficacy of Trm and other MEKi’s.

项目概要/摘要 Ras-Raf-MEK-ERK 通路的持续过度激活导致超过 30% 的人类肿瘤发生 Trametinib (Trm) 是 MEK1 的高度选择性抑制剂，MEK1 是多功能的唯一上游激活剂。 促生存激酶 ERK1/2 通常与达拉非尼联合使用以延长患者的生命。 黑色素瘤；其对其他常见肿瘤类型（包括三阴性乳腺癌（TNBC））的疗效正在研究中 Trm 通常具有良好的耐受性，但可能会导致心肌病，从而导致心脏病。 高达 11% 的病例出现心力衰竭（HF），而 Trm 相关心脏毒性的机制尚不清楚。 初步数据显示，14 天的 Trm 治疗消除了小鼠心肌 ERK1/2 激活并诱导 可逆性心脏收缩功能障碍，其特征是线粒体丰度减少和受损 Trm 处理的小鼠心脏的体内氧化磷酸化显着降低。 线粒体转录和免疫反应途径的增加在分子上与其他途径不同 心衰病因。原代心肌细胞体外暴露于 Trm 会导致线粒体损伤并被激活。 我们目前的理解并没有预测到这些令人惊讶的影响。 MEK-ERK心肌细胞生物学或通过我们对MEK抑制剂抗癌机制的理解 （MEKi 的）在这里，我们将使用 3 个具体目标来检验 MEK-ERK 抑制会损害这一中心假设。 OXPHOS 诱导线粒体损伤，导致先天免疫激活，并且这些效应共同作用 对 Trm 的心脏毒性和抗癌功效都有贡献 在机制目标 1 中，我们会发现 Trm 是否有效。 通过损害氧化磷酸化和诱导氧化应激来诱导线粒体损伤。目标 2。 将确定 MEK 功能的遗传或药理学丧失是否足以诱导心肌细胞 使用心肌细胞 MEK1 缺陷的新型小鼠模型和 FDA 批准的其他模型进行线粒体损伤 药理学 MEKi 的目标 3 将测试 Trm 诱导的线粒体毒性是否激活先天免疫。 使用经过验证的 TNBC 小鼠模型和临床相关的模型对心肌细胞和癌细胞的反应 这些研究将确定是否激活模式识别受体。 通过线粒体损伤相关的分子模式有助于 Trm 心脏毒性或抗癌功效， 并将确定在免疫检查点抑制剂中添加 Trm 是否会增加心脏毒性风险。 拟议的实验有可能影响心肌生物学和癌症治疗领域 相关但不同的方式：（1）扩展我们对心肌细胞线粒体MEK-ERK调节的理解 (2) 确定导致 Trm 心脏毒性的分子过程； 线粒体毒性和先天免疫激活有助于 Trm 和其他 MEKi 的抗癌功效。