Understanding EGF receptor activation by growth factors and oncogenic mutations
Understanding EGF receptor activation by growth factors and oncogenic mutations
批准号:
10393025
负责人:
KATHRYN M FERGUSON
金额:
$52.07万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
未结题
起止时间:
2015-08-18 至 2025-04-30
关键词:
AREG geneAffectAffinityAgonistAntibodiesBehaviorBindingBiochemicalBiophysicsCancer EtiologyCellsClinicClinicalCoupledCrystallizationDataDatabasesDeuteriumDimerizationDiseaseEGF geneERBB3 geneEnzymatic BiochemistryEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorEpiregulinExonsExtracellular DomainFamily memberFc ReceptorFundingG-Protein-Coupled ReceptorsGene AmplificationGenerationsGlioblastomaGoalsGrowth FactorHydrogenKineticsLigandsMalignant NeoplasmsMalignant neoplasm of lungMass Spectrum AnalysisMeasuresMicroprocessorMolecular ConformationMutateMutationNatureOncogenicOutcomePatientsPharmaceutical PreparationsPhosphotransferasesPropertyReceptor ActivationReceptor Protein-Tyrosine KinasesReceptor SignalingReportingResistanceResolutionSignal TransductionSpecificityStructureTestingTherapeutic InterventionTransmembrane DomainTyrosine Kinase DomainTyrosine Kinase InhibitorVariantWorkbasecancer celldimerepigenextracellularinhibitorinhibitor therapyinsightkinase inhibitormutantnovel therapeutic interventionreceptorresponsesuccesstargeted treatment
中文摘要
表皮生长因子受体(EGFR)通常被描述为一种“原型”受体酪氨酸激酶
(RTK)。作为第一个单跨膜结构域受体之一,其配体诱导的二聚化是
据报道,EGFR(和其他RTK)的“传统”观点是二元“关”/“开”开关。我们以前的
的工作,以及最近对类似受体的工作,相反,认为这种类型的受体的信号是
EGFR和其他受体可以区分不同的配体。的确,
我们发现不同的EGFR激活配体可以诱导具有不同结构的受体二聚体,
不同的信号动力学和正交细胞结果。值得注意的是,定义蛋白质的关键残基
这些二聚体结构之间的差异与细胞外EGFR突变的热点一致
胶质母细胞瘤因此,我们在此假设GBM中的EGFR突变可能至少部分地发挥其作用。
通过改变对不同EGFR配体的信号应答的性质来影响。这将打开
如果可以开发抗体或其他药物,
通过与G蛋白偶联的偏向性激动剂类比,将它们重新编程为“变构微处理器”。
受体。
胶质母细胞瘤和肺癌对EGFR抑制剂的原发性耐药是一个重要的临床问题
这限制了现有EGFR靶向酪氨酸激酶抑制剂(TKI)的成功。静态结构视图
激酶结构域还不能令人满意地解释TKI抑制不同细胞因子的相对能力。
变异体-原发性耐药和突变体选择性(例如奥希替尼)的起源尚不清楚,
很难解决。获得性TKI耐药性的新实例遭受同样的问题。我们的研究使用
氢氘交换质谱(HDX-MS)和酶学研究表明,
在于突变和TKI本身对结构动力学的影响-特别是在
第三代共价EGFR抑制剂的情况下,与他们的目标,在多个步骤。
在此背景下,该提案的关键总体目标是确定EGFR变体的特定行为
这可以解释它们改变的信号特性和对抑制剂的敏感性。我们应用
一系列的生物物理,结构,生物化学和细胞方法来询问信号在几个
分辨率的水平。除了回答EGFR的关键机制问题外,我们的结果还应阐明
治疗干预的潜在新途径。我们的具体目标提出以下问题:
1 EGFR家族成员的疾病相关细胞外突变如何影响信号传导特异性
动力学?
2结构动力学能否解释EGFR 19号外显子变异体在肺组织中的原发性激酶抑制剂耐药
癌症和第三代共价抑制剂的选择性?
英文摘要
The epidermal growth factor receptor (EGFR) is often described as a ‘prototypic’ receptor tyrosine kinase
(RTK). As one of the first single transmembrane domain receptors for which ligand-induced dimerization was
reported, the ‘traditional’ view of EGFR (and other RTKs) has been of a binary ‘off’/‘on’ switch. Our previous
work, together with recent work on similar receptors, instead argues that signaling by receptors of this type is
much more ‘graded’ – and that EGFR and other receptors can discriminate between different ligands. Indeed,
we showed that different EGFR-activating ligands can induce receptor dimers with distinct structures – leading
to different signaling kinetics and orthogonal cellular outcomes. Remarkably, the key residues that define the
differences between the structures of these dimers coincide with the hotspots for extracellular EGFR mutations
in glioblastoma. We therefore hypothesize here that EGFR mutations in GBM may exert at least part of their
effect by altering the nature of the signaling response to different EGFR ligands. This would open the
possibility of ‘correcting’ EGFR signaling in cancer if antibodies or other agents could be developed to
reprogram them as ‘allosteric microprocessors’ by analogy with biased agonists for G-protein coupled
receptors.
Primary resistance to EGFR inhibitors in glioblastoma and in lung cancer is an important clinical problem
that limits success with existing EGFR-targeted tyrosine kinase inhibitors (TKIs). Static structural views of
kinase domains have not allowed satisfying explanations for the relative abilities of TKIs to inhibit different
variants – leaving the origins of primary resistance and of mutant selectivity (e.g. of osimertinib) unclear and
difficult to solve. New instances of acquired TKI resistance suffer from the same problem. Our studies using
hydrogen-deuterium exchange mass spectrometry (HDX-MS) alongside enzymology suggest that the key may
lie in the effects of both the mutations and the TKIs themselves on structural dynamics – particularly in the
case of 3rd generation covalent EGFR inhibitors that associate with their targets in multiple steps.
With this background, the key overall goal of this proposal is to identify specific behavior of EGFR variants
seen in cancer that can explain their altered signaling properties and altered sensitivity to inhibitors. We apply
a range of biophysical, structural, biochemical, and cellular approaches to interrogate signaling at several
levels of resolution. In addition to answering key mechanistic questions for EGFR, our results should illuminate
potential new avenues for therapeutic intervention. Our Specific Aims ask the following questions:
1 How do disease-associated extracellular mutations in EGFR family members affect signaling specificity
and kinetics?
2 Can structural dynamics explain primary kinase inhibitor resistance of exon 19 EGFR variants in lung
cancer, and selectivity of 3rd generation covalent inhibitors?
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Yale Head and Neck Cancer SPORE Career Enhancement Program
-
批准号:10669006
-
项目类别:
-
资助金额:$11.63万
-
财政年份:2020
-
负责人:KATHRYN M FERGUSON
-
依托单位:
Yale Head and Neck Cancer SPORE Career Enhancement Program
-
批准号:10267851
-
项目类别:
-
资助金额:$11.63万
-
财政年份:2020
-
负责人:KATHRYN M FERGUSON
-
依托单位:
Yale Head and Neck Cancer SPORE Career Enhancement Program
-
批准号:10441513
-
项目类别:
-
资助金额:$11.35万
-
财政年份:2020
-
负责人:KATHRYN M FERGUSON
-
依托单位:
Regulation of Tie2 activation by homo- and hetero-oligomerization
-
批准号:9287102
-
项目类别:
-
资助金额:$38.32万
-
财政年份:2017
-
负责人:KATHRYN M FERGUSON
-
依托单位:
Regulation of Tie2 activation by homo- and hetero-oligomerization
-
批准号:9892964
-
项目类别:
-
资助金额:$38.32万
-
财政年份:2017
-
负责人:KATHRYN M FERGUSON
-
依托单位:
Analysis of active and inactive EGFR conformations
-
批准号:9181106
-
项目类别:
-
资助金额:$13.96万
-
财政年份:2016
-
负责人:KATHRYN M FERGUSON
-
依托单位:
Understanding EGF receptor activation by growth factors and oncogenic mutations
-
批准号:8944333
-
项目类别:
-
资助金额:$49.86万
-
财政年份:2015
-
负责人:KATHRYN M FERGUSON
-
依托单位:
Understanding EGF receptor activation by growth factors and oncogenic mutations
-
批准号:10222588
-
项目类别:
-
资助金额:$53.97万
-
财政年份:2015
-
负责人:KATHRYN M FERGUSON
-
依托单位:
Understanding EGF receptor activation by growth factors and oncogenic mutations
-
批准号:9321880
-
项目类别:
-
资助金额:$53.57万
-
财政年份:2015
-
负责人:KATHRYN M FERGUSON
-
依托单位:
Understanding EGF receptor activation by growth factors and oncogenic mutations
-
批准号:10615073
-
项目类别:
-
资助金额:$51.16万
-
财政年份:2015
-
负责人:KATHRYN M FERGUSON
-
依托单位:
Signaling mechanisms of RTKs with membrane-proximal fibronectin type III domains
-
批准号:8751107
-
项目类别:
-
资助金额:$8.0万
-
财政年份:2014
-
负责人:KATHRYN M FERGUSON
-
依托单位:
STRUCTURAL STUDIES OF MACROMOLECULAR SIGNALING COMPLEXES
-
批准号:8171489
-
项目类别:
-
资助金额:$2.42万
-
财政年份:2010
-
负责人:KATHRYN M FERGUSON
-
依托单位:
STRUCTURAL STUDIES OF MACROMOLECULAR SIGNALING COMPLEXES
-
批准号:7955544
-
项目类别:
-
资助金额:$2.72万
-
财政年份:2009
-
负责人:KATHRYN M FERGUSON
-
依托单位:
STRUCTURAL STUDIES OF MACROMOLECULAR SIGNALING COMPLEXES
-
批准号:7721293
-
项目类别:
-
资助金额:$4.61万
-
财政年份:2008
-
负责人:KATHRYN M FERGUSON
-
依托单位:
STRUCTURAL STUDIES OF MACROMOLECULAR SIGNALING COMPLEXES
-
批准号:7598544
-
项目类别:
-
资助金额:$2.83万
-
财政年份:2007
-
负责人:KATHRYN M FERGUSON
-
依托单位:
STRUCTURES OF THE EXTRACELLULAR DOMAIN OF THE EPIDERMAL GROWTH FACTOR
-
批准号:7357732
-
项目类别:
-
资助金额:$1.31万
-
财政年份:2006
-
负责人:KATHRYN M FERGUSON
-
依托单位:
Analysis of active and inactive EGFR conformations
-
批准号:8040305
-
项目类别:
-
资助金额:$23.46万
-
财政年份:2005
-
负责人:KATHRYN M FERGUSON
-
依托单位:
Analysis of active and inactive EGFR conformations
-
批准号:7241581
-
项目类别:
-
资助金额:$23.75万
-
财政年份:2005
-
负责人:KATHRYN M FERGUSON
-
依托单位:
Analysis of active and inactive EGFR conformations
-
批准号:7418929
-
项目类别:
-
资助金额:$23.75万
-
财政年份:2005
-
负责人:KATHRYN M FERGUSON
-
依托单位:
Analysis of active and inactive EGFR conformations
-
批准号:7081431
-
项目类别:
-
资助金额:$24.45万
-
财政年份:2005
-
负责人:KATHRYN M FERGUSON
-
依托单位:
海外基金