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

基本信息

  • 批准号:
    10753009
  • 负责人:
  • 金额:
    $ 53.36万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Brian C Jensen其他文献

HIGH RESOLUTION MAPPING OF THE ALPHA-1A-ADRENERGIC RECEPTOR SUBTYPE IN MALE MOUSE UROGENITAL ORGANS
  • DOI:
    10.1016/s0022-5347(09)60425-0
  • 发表时间:
    2009-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Chihiro Hosoda;Bat-Erdene Myagmar;Philip M Swigart;Brian C Jensen;Paul C Simpson
  • 通讯作者:
    Paul C Simpson

Brian C Jensen的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Brian C Jensen', 18)}}的其他基金

Metabolic mechanisms of cardioprotection through alpha-1A adrenergic receptor activation
通过 α-1A 肾上腺素受体激活保护心脏的代谢机制
  • 批准号:
    10587727
  • 财政年份:
    2017
  • 资助金额:
    $ 53.36万
  • 项目类别:
Metabolic mechanisms of cardioprotection through alpha-1A adrenergic receptor activation
通过 α-1A 肾上腺素受体激活保护心脏的代谢机制
  • 批准号:
    10318139
  • 财政年份:
    2017
  • 资助金额:
    $ 53.36万
  • 项目类别:
Metabolic mechanisms of cardioprotection through alpha-1A adrenergic receptor activation
通过 α-1A 肾上腺素受体激活保护心脏的代谢机制
  • 批准号:
    10067377
  • 财政年份:
    2017
  • 资助金额:
    $ 53.36万
  • 项目类别:
Alpha-1-Adrenergic Receptor Subtypes in the Cells of the Human Heart
人类心脏细胞中的 Alpha-1-肾上腺素能受体亚型
  • 批准号:
    8131703
  • 财政年份:
    2009
  • 资助金额:
    $ 53.36万
  • 项目类别:
Alpha-1-Adrenergic Receptor Subtypes in the Cells of the Human Heart
人类心脏细胞中的 Alpha-1-肾上腺素能受体亚型
  • 批准号:
    8496578
  • 财政年份:
    2009
  • 资助金额:
    $ 53.36万
  • 项目类别:
Alpha-1-Adrenergic Receptor Subtypes in the Cells of the Human Heart
人类心脏细胞中的 Alpha-1-肾上腺素能受体亚型
  • 批准号:
    7707444
  • 财政年份:
    2009
  • 资助金额:
    $ 53.36万
  • 项目类别:
Alpha-1-Adrenergic Receptor Subtypes in the Cells of the Human Heart
人类心脏细胞中的 Alpha-1-肾上腺素能受体亚型
  • 批准号:
    8294717
  • 财政年份:
    2009
  • 资助金额:
    $ 53.36万
  • 项目类别:
Alpha-1-Adrenergic Receptor Subtypes in the Cells of the Human Heart
人类心脏细胞中的 Alpha-1-肾上腺素能受体亚型
  • 批准号:
    7919951
  • 财政年份:
    2009
  • 资助金额:
    $ 53.36万
  • 项目类别:

相似海外基金

Molecular insights into the allosteric regulation of opioid receptors
阿片受体变构调节的分子见解
  • 批准号:
    DE240100931
  • 财政年份:
    2024
  • 资助金额:
    $ 53.36万
  • 项目类别:
    Discovery Early Career Researcher Award
Allosteric regulation of lysine degradation as a novel pathophysiological mechanism in glutaric aciduria type 1
赖氨酸降解的变构调节作为 1 型戊二酸尿症的一种新的病理生理机制
  • 批准号:
    10720740
  • 财政年份:
    2023
  • 资助金额:
    $ 53.36万
  • 项目类别:
Elucidating the Mechanism for Allosteric Regulation of SIRT1 through the N-terminal Region
阐明 SIRT1 通过 N 末端区域变构调节的机制
  • 批准号:
    10627735
  • 财政年份:
    2023
  • 资助金额:
    $ 53.36万
  • 项目类别:
Allosteric Regulation of Actin Capping Protein: Mechanism and Significance
肌动蛋白加帽蛋白的变构调节:机制和意义
  • 批准号:
    10330809
  • 财政年份:
    2022
  • 资助金额:
    $ 53.36万
  • 项目类别:
Allosteric Regulation of Actin Capping Protein: Mechanism and Significance
肌动蛋白加帽蛋白的变构调节:机制和意义
  • 批准号:
    10797746
  • 财政年份:
    2022
  • 资助金额:
    $ 53.36万
  • 项目类别:
Structural and functional studies of allosteric regulation of metabolic enzymes
代谢酶变构调节的结构和功能研究
  • 批准号:
    RGPIN-2020-04281
  • 财政年份:
    2022
  • 资助金额:
    $ 53.36万
  • 项目类别:
    Discovery Grants Program - Individual
Allosteric Regulation of Actin Capping Protein: Mechanism and Significance
肌动蛋白加帽蛋白的变构调节:机制和意义
  • 批准号:
    10552651
  • 财政年份:
    2022
  • 资助金额:
    $ 53.36万
  • 项目类别:
Allosteric regulation of human cystathionine beta-synthase
人胱硫醚β-合酶的变构调节
  • 批准号:
    10602404
  • 财政年份:
    2022
  • 资助金额:
    $ 53.36万
  • 项目类别:
Allosteric regulation of human cystathionine beta-synthase
人胱硫醚β-合酶的变构调节
  • 批准号:
    10381000
  • 财政年份:
    2022
  • 资助金额:
    $ 53.36万
  • 项目类别:
Structural basis for allosteric regulation of RyR1
RyR1 变构调节的结构基础
  • 批准号:
    10366087
  • 财政年份:
    2021
  • 资助金额:
    $ 53.36万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了