Feedback regulation and functional output of the RAS/RAF/MEK/MAPK pathway in huma
人RAS/RAF/MEK/MAPK通路的反馈调节和功能输出
基本信息
- 批准号:7788247
- 负责人:
- 金额:$ 17.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-21 至 2014-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingBRAF geneBindingBiological ProcessBreast CarcinomaCell LineCell NucleusCell ProliferationCellsClinical TrialsDataDisabled PersonsDown-RegulationDrug usageERBB2 geneETV1 geneETV4 geneEffectivenessEpidermal Growth Factor ReceptorEventExposure toFamilyFamily memberFeedbackFractionationGene ExpressionGenesGenetic TranscriptionGenomeGoalsGrowthHumanImmunoblottingImpairmentJUN geneMAP Kinase GeneMAP Kinase Kinase Kinase 1MAPK1 geneMEK inhibitionMEKKsMEKsMeasurementMeasuresMediator of activation proteinMitogen-Activated Protein KinasesMusMutationNuclearOncogenicOutputPathway interactionsPatientsPatternPhenotypePhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPhysiologicalPrincipal InvestigatorProtein KinaseProtein Tyrosine KinaseProteinsRNA InterferenceReceptor Protein-Tyrosine KinasesRefractoryRegulationResearchResearch PersonnelResearch ProposalsResistanceRoleSignal PathwaySignal TransductionSmall Interfering RNASystemTestingTetracyclinesTranscriptTransfectionUp-Regulationbasecell growthcell transformationgain of functionhuman MAP3K1 proteinimmunocytochemistryin vivoin vivo Modelinhibitor/antagonistkinase inhibitormelanomamutantneoplastic celloverexpressionprogramspromoterprotein expressionpublic health relevancereceptorresponseselective expressionsmall hairpin RNAsmall moleculetissue culturetranscription factortumortumor growthtumor xenograftvector control
项目摘要
DESCRIPTION (provided by applicant): BRAF mutations occur in a significant proportion of human tumors, and represent a mechanism of constitutive activation of the MAPK pathway. We have demonstrated that activating mutations of BRAF confer sensitivity to small molecule inhibitors of the pathway. In contrast, we showed that HER2-overexpressing breast carcinomas were resistant to MEK inhibition, despite effective pharmacologic inhibition of MAPK activity. Our preliminary data suggest that tumors with HER kinase activation (and WT BRAF) and those with oncogenic BRAF have similar levels of phosphorylated ERK; however, BRAF mutant tumors have higher levels of phosphorylated MEK and selected MEK-ERK dependent transcripts. Further, MEK inhibitor-induced feedback upregulation of the pathway is seen only in the receptor-activated tumors, but not in tumors with activating BRAF mutation. We hypothesize that increased output of the MAPK pathway in B- RAF mutant tumors compared to HER kinase-activated tumors is due to the impairment of feedback inhibition of the pathway, upstream of, and/or at the level of, RAF. We hypothesize that disabling of upstream feedback in BRAF mutant tumors causes an increase in pathway throughput, resulting in increased expression of ERK effectors, and targets responsible for pathway feedback (DUSP, SPRY proteins). This increase in DUSPs (MAP kinase phosphatases) may be critical for the downregulation of ERK to physiologically tolerated levels. The increase in both feedback and effector proteins may together be responsible for aspects of the transformed phenotype. In this proposal, we describe further preliminary data which support these assertions, and describe a research plan to determine the mechanism of feedback response to MEK inhibition. We will determine whether phosphorylated ERK represents an accurate reflection of pathway activation. We will use small molecule inhibitors of the pathway, as well as RNA interference to determine the role of critical proteins in the feedback program. Finally, we will develop isogenic systems transformed by oncogenic BRAF and activated receptor tyrosine kinases to determine if specific feedback and effector protein expression patterns can be generated. The translational goals of these studies are to identify feedback pathways modulating the response to RAF and MEK inhibitors which will impact the effectiveness of these compounds in clinical trials.
PUBLIC HEALTH RELEVANCE: The RAS-RAF-MEK-ERK signaling pathway is an important regulator of tumor cell growth and proliferation. The goals of this research proposal are to understand feedback mechanisms which regulate the activation of this pathway. Understanding this regulatory mechanism will help investigators use drugs which target this pathway to select patients whose tumors are most likely to respond to them. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page
描述(由申请人提供):BRAF突变发生在很大比例的人类肿瘤中,并且代表了MAPK通路的组成激活机制。我们已经证明,BRAF的激活突变对该途径的小分子抑制剂具有敏感性。相反,我们发现her2过表达的乳腺癌对MEK抑制有抗性,尽管MAPK活性有有效的药理抑制。我们的初步数据表明,具有HER激酶激活(和WT BRAF)的肿瘤和具有致癌BRAF的肿瘤具有相似的磷酸化ERK水平;然而,BRAF突变肿瘤具有更高水平的磷酸化MEK和选择性的MEK- erk依赖转录物。此外,MEK抑制剂诱导的通路反馈上调仅见于受体激活的肿瘤,而未见于激活BRAF突变的肿瘤。我们假设,与HER激酶激活的肿瘤相比,B- RAF突变肿瘤中MAPK通路的输出增加是由于该通路在RAF上游和/或RAF水平上的反馈抑制受损。我们假设BRAF突变肿瘤中上游反馈的失能会导致通路通量增加,从而导致ERK效应物和负责通路反馈的靶标(DUSP, SPRY蛋白)的表达增加。DUSPs (MAP激酶磷酸酶)的增加可能是ERK下调到生理耐受水平的关键。反馈蛋白和效应蛋白的增加可能共同负责转化表型的各个方面。在本文中,我们进一步描述了支持这些断言的初步数据,并描述了一项研究计划,以确定对MEK抑制的反馈反应机制。我们将确定磷酸化的ERK是否代表了通路激活的准确反映。我们将使用该途径的小分子抑制剂,以及RNA干扰来确定关键蛋白质在反馈程序中的作用。最后,我们将开发由致癌BRAF和激活受体酪氨酸激酶转化的等基因系统,以确定是否可以产生特定的反馈和效应蛋白表达模式。这些研究的转化目标是确定反馈通路调节对RAF和MEK抑制剂的反应,这将影响这些化合物在临床试验中的有效性。
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)
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Christine Anne Pratilas其他文献
Christine Anne Pratilas的其他文献
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{{ truncateString('Christine Anne Pratilas', 18)}}的其他基金
Advancing RAS pathway targeted therapy in NF1-MPNST: effects of SHP2 and CDK4/6 inhibitors on the tumor and the tumor immune microenvironment
推进NF1-MPNST的RAS通路靶向治疗:SHP2和CDK4/6抑制剂对肿瘤和肿瘤免疫微环境的影响
- 批准号:
10660326 - 财政年份:2023
- 资助金额:
$ 17.32万 - 项目类别:
Feedback regulation and functional output of the RAS/RAF/MEK/MAPK pathway in huma
人RAS/RAF/MEK/MAPK通路的反馈调节和功能输出
- 批准号:
8128465 - 财政年份:2009
- 资助金额:
$ 17.32万 - 项目类别:
Feedback regulation and functional output of the RAS/RAF/MEK/MAPK pathway in huma
人RAS/RAF/MEK/MAPK通路的反馈调节和功能输出
- 批准号:
8534035 - 财政年份:2009
- 资助金额:
$ 17.32万 - 项目类别:
Feedback regulation and functional output of the RAS/RAF/MEK/MAPK pathway in huma
人RAS/RAF/MEK/MAPK通路的反馈调节和功能输出
- 批准号:
8931249 - 财政年份:2009
- 资助金额:
$ 17.32万 - 项目类别:
Feedback regulation and functional output of the RAS/RAF/MEK/MAPK pathway in huma
人RAS/RAF/MEK/MAPK通路的反馈调节和功能输出
- 批准号:
7937058 - 财政年份:2009
- 资助金额:
$ 17.32万 - 项目类别:
Feedback regulation and functional output of the RAS/RAF/MEK/MAPK pathway in huma
人RAS/RAF/MEK/MAPK通路的反馈调节和功能输出
- 批准号:
8321029 - 财政年份:2009
- 资助金额:
$ 17.32万 - 项目类别:
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