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.

项目总结/文摘