The structural and functional basis of MET exon 14 activation and acquired drug resistance
MET 外显子 14 激活和获得性耐药的结构和功能基础
基本信息
- 批准号:9892984
- 负责人:
- 金额:$ 40.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AdenocarcinomaAffinityAllelesAmericanAnimalsAutomobile DrivingBindingBiologicalBiologyCancer EtiologyCancer PatientCellsClinicalColon CarcinomaDevelopmentDiseaseDrug ModelingsDrug TargetingEpidermal Growth Factor ReceptorEpithelialEpitheliumEventExonsFosteringFrequenciesGene MutationGenerationsGenesGeneticGenomicsGenotypeGoalsGrantImmunotherapyIn VitroKnowledgeLeadLungLung AdenocarcinomaMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of prostateMediatingMedical OncologistMesenchymalMethodsMissense MutationModelingMolecular ConformationMutateMutationNon-Small-Cell Lung CarcinomaOncogenesOncoproteinsOutcomePatientsPharmaceutical PreparationsPhosphotransferasesPlant RootsPlayPopulationPredispositionProtein AnalysisProtein KinasePublishingReceptor Protein-Tyrosine KinasesReceptor SignalingRecombinantsRecurrenceResearchResistanceRoleRouteSignal TransductionStructureTestingThe Cancer Genome AtlasTimeacquired drug resistancecancer typeclinical carecrizotinibdrug sensitivitydruggable targetexperiencegene discoveryimprovedin vivoin vivo Modelinhibitor/antagonistinnovationkinase inhibitormalignant breast neoplasmmouse modelprecision medicinepressurepreventprogrammed cell death ligand 1receptorresistance mechanismresistance mutationresponsetargeted treatmenttherapeutic developmenttherapy developmenttumor
项目摘要
Project Summary/Abstract
Summary: Lung cancer is the largest cancer killer but is also a heterogeneous disease in which different
oncoproteins contribute to genetic subtypes, some of which carry specific treatments. Despite favorable
outcomes when therapies are matched to driving oncogenes, only small fraction of lung cancer patients are
treated in a targeted manner. Our goal is to optimize targeted therapy for the large proportion of lung cancer
patients harboring activating mutations in the Mesenchymal Epithelial Transformation (MET) gene.
Background: MET mutations are the most recent addition to the list of druggable, recurrently mutated kinases in
nonsmall cell lung cancer (NSCLC). We have recently defined the frequency of MET aberrations in NSCLC,
and identified exon 14 deletion in the juxtamembrane domain of MET as the most common somatic MET event.
The mechanism for its action and its susceptibility to existing targeted MET therapies is however poorly defined,
preventing targeted treatment of this large population of NSCLC patients.
Methods: We will focus on the signaling and structural effects MET exon 14 mutations impart with the goal of
understanding the mechanism of action underlying selection for this mutation in NSCLC. We will first
characterize the mechanism by which the juxtamembrane segment of MET regulates the kinase, using purified
recombinant MET fragments from its intracellular domain. Next, we will study how exon 14 deletions influence
MET inhibitors' binding and whether mutation confers affinity for specific classes of kinase inhibitors. Finally,
we will model resistance mutations to first generation (Type I) MET inhibitors in vivo, and suggest strategies to
overcome them using targeted approaches with Type II inhibitors and “off-MET” drug targets.
Impact: This project focuses on a common and understudied mutation in lung cancer, the most lethal cancer
type, by far. Thousands of Americans die each year with MET-mutated lung cancer, and often do so without
being considered for targeted therapy against their tumor's genotype. We will clarify the role MET mutation
plays in lung cancer and will structurally define how the most common mutations activate this oncoprotein.
This project will foster development of therapies targeting MET exon 14 mutations, and optimize approaches to
targeting the most common anticipated routes of resistance.
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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Eric Collisson其他文献
Eric Collisson的其他文献
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{{ truncateString('Eric Collisson', 18)}}的其他基金
Optimizing Pancreatic Cancer Management with Next Generation Imaging and Liquid Biopsy
利用下一代成像和液体活检优化胰腺癌治疗
- 批准号:
10376196 - 财政年份:2021
- 资助金额:
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Optimizing Pancreatic Cancer Management with Next Generation Imaging and Liquid Biopsy
利用下一代成像和液体活检优化胰腺癌治疗
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了解 1,2,4-三氧戊环在癌症中的功效和 Fe(II) 促进的激活
- 批准号:
10374172 - 财政年份:2021
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$ 40.99万 - 项目类别:
Understanding Efficacy and Fe(II)-Promoted Activation of 1,2,4-Trioxolanes in Cancer
了解 1,2,4-三氧戊环在癌症中的功效和 Fe(II) 促进的激活
- 批准号:
10622460 - 财政年份:2021
- 资助金额:
$ 40.99万 - 项目类别:
The structural and functional basis of MET exon 14 activation and acquired drug resistance
MET 外显子 14 激活和获得性耐药的结构和功能基础
- 批准号:
9754544 - 财政年份:2019
- 资助金额:
$ 40.99万 - 项目类别:
The structural and functional basis of MET exon 14 activation and acquired drug resistance
MET 外显子 14 激活和获得性耐药的结构和功能基础
- 批准号:
10375379 - 财政年份:2019
- 资助金额:
$ 40.99万 - 项目类别:
Optimizing Treatment Approaches to Lung Cancers Harboring MET Exon 14 mutations
优化含有 MET 外显子 14 突变的肺癌的治疗方法
- 批准号:
9891979 - 财政年份:2019
- 资助金额:
$ 40.99万 - 项目类别:
Optimizing Treatment Approaches to Lung Cancers Harboring MET Exon 14 mutations
优化含有 MET 外显子 14 突变的肺癌的治疗方法
- 批准号:
9763138 - 财政年份:2019
- 资助金额:
$ 40.99万 - 项目类别:
Optimizing Treatment Approaches to Lung Cancers Harboring MET Exon 14 mutations
优化含有 MET 外显子 14 突变的肺癌的治疗方法
- 批准号:
10589867 - 财政年份:2019
- 资助金额:
$ 40.99万 - 项目类别:
The structural and functional basis of MET exon 14 activation and acquired drug resistance
MET 外显子 14 激活和获得性耐药的结构和功能基础
- 批准号:
10580077 - 财政年份:2019
- 资助金额:
$ 40.99万 - 项目类别:
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