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
- 来源:
- 关键词:Adverse effectsAllosteric RegulationBRAF geneBioenergeticsBiologyBreast Cancer CellCardiacCardiac MyocytesCardiomyopathiesCardiotoxicityCessation of lifeClinical TrialsCombined Modality TherapyCommon NeoplasmComplexCoupledDataElectron TransportEtiologyExtracellular Signal Regulated KinasesFDA approvedFunctional disorderFutureGeneticHeartHeart InjuriesHeart MitochondriaHeart failureHumanImmuneImmune checkpoint inhibitorImmune responseImpairmentIn VitroInflammationInflammatoryInjuryInnate Immune ResponseLifeMAP2K1 geneMAPK3 geneMEK inhibitionMEKsMalignant NeoplasmsMediatingMitochondriaMolecularMusMuscle FibersMyocardialOxidative PhosphorylationOxidative StressOxidative Stress InductionPathway interactionsPatientsPatternPattern recognition receptorPermeabilityPhasePhenotypePhosphorylationPhysiologyProcessPublishingRas/RafReactionRegulationResearch PersonnelRiskRoleSTAT3 geneTestingTherapeuticToxic effectTranscriptWorkanti-cancercancer cellcancer therapycardiovascular effectsclinically relevantcombination cancer therapycomplex IVcytokinediagnostic platformexperimental studygenetic manipulationimmune activationin vivoinhibitorinjuredinnate immune pathwaysmelanomamouse modelnovelpharmacologicpre-clinicalprogrammed cell death ligand 1respiratorytargeted cancer therapytargeted treatmenttranscriptome sequencingtranscriptomicstriple-negative invasive breast carcinomatumortumorigenesis
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)
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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
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{{ 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:
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