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:9754544
- 负责人:
- 金额:$ 40.81万
- 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 ReceptorEpithelialEventExonsFosteringFrequenciesGene MutationGenerationsGenesGeneticGenomicsGenotypeGoalsGrantImmunotherapyIn VitroKnowledgeLeadLungLung AdenocarcinomaMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of prostateMediatingMedical OncologistMesenchymalMethodsMissense MutationModelingMolecular ConformationMutateMutationNon-Small-Cell Lung CarcinomaOncogenesOncoproteinsOutcomePDCD1LG1 genePatientsPharmaceutical 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 medicinepressurepreventreceptorresistance 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/摘要
摘要:肺癌是最大的癌症杀手,但也是一种异质性疾病,
癌蛋白有助于基因亚型,其中一些携带特定的治疗。尽管有利
当治疗与驱动癌基因相匹配时,只有一小部分肺癌患者
以有针对性的方式治疗。我们的目标是优化大比例肺癌的靶向治疗
间充质上皮转化(MET)基因中携带激活突变的患者。
背景:MET突变是最近加入到可药物化的、反复突变的激酶列表中的,
非小细胞肺癌(NSCLC)。我们最近确定了NSCLC中MET畸变的频率,
并且鉴定MET的质膜结构域中的外显子14缺失为最常见的体细胞MET事件。
然而,其作用机制及其对现有靶向MET疗法的敏感性尚不明确,
阻止对这一庞大的NSCLC患者群体进行靶向治疗。
方法:我们将重点关注MET外显子14突变的信号传导和结构效应,
了解NSCLC中这种突变选择的潜在作用机制。我们将首先
用纯化的MET膜片段表征MET膜片段调节激酶的机制,
重组MET片段从其胞内结构域。接下来,我们将研究外显子14缺失如何影响
MET抑制剂的结合以及突变是否赋予对特定类别的激酶抑制剂的亲和力。最后,
我们将在体内模拟第一代(I型)MET抑制剂的耐药突变,并提出策略,
使用II型抑制剂和“脱MET”药物靶点的靶向方法克服它们。
影响:该项目的重点是肺癌中一种常见且未充分研究的突变,肺癌是最致命的癌症。
类型,到目前为止。每年有成千上万的美国人死于MET突变的肺癌,而且通常没有
正在考虑针对他们的肿瘤基因型进行靶向治疗。我们将阐明MET突变的作用
在肺癌中起作用,并将在结构上定义最常见的突变如何激活这种癌蛋白。
该项目将促进靶向MET外显子14突变的疗法的开发,并优化方法,
针对最常见的预期抵抗路线。
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 }}
Eric Collisson其他文献
Eric Collisson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('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:
$ 40.81万 - 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:
10374172 - 财政年份:2021
- 资助金额:
$ 40.81万 - 项目类别:
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:
10584523 - 财政年份:2021
- 资助金额:
$ 40.81万 - 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:
$ 40.81万 - 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:
9892984 - 财政年份:2019
- 资助金额:
$ 40.81万 - 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:
$ 40.81万 - 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:
$ 40.81万 - 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:
$ 40.81万 - 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:
$ 40.81万 - 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:
$ 40.81万 - 项目类别:
相似海外基金
Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
- 批准号:
23H01982 - 财政年份:2023
- 资助金额:
$ 40.81万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
- 批准号:
23KJ0116 - 财政年份:2023
- 资助金额:
$ 40.81万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
- 批准号:
10682794 - 财政年份:2023
- 资助金额:
$ 40.81万 - 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
- 批准号:
10598276 - 财政年份:2023
- 资助金额:
$ 40.81万 - 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233343 - 财政年份:2023
- 资助金额:
$ 40.81万 - 项目类别:
Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233342 - 财政年份:2023
- 资助金额:
$ 40.81万 - 项目类别:
Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
- 批准号:
479363 - 财政年份:2023
- 资助金额:
$ 40.81万 - 项目类别:
Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
- 批准号:
10681989 - 财政年份:2023
- 资助金额:
$ 40.81万 - 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
- 批准号:
2237240 - 财政年份:2023
- 资助金额:
$ 40.81万 - 项目类别:
Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
- 批准号:
2305592 - 财政年份:2023
- 资助金额:
$ 40.81万 - 项目类别:
Continuing Grant