Defining the role of FAM83B in lung cancer using a new mouse model

使用新的小鼠模型定义 FAM83B 在肺癌中的作用

基本信息

批准号：
10373095
负责人：
MARK W. JACKSON
金额：
$ 8.05万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10373095
关键词：
Ablation Automobile Driving Binding Biological Markers Cancer cell line Complex Development Dose-Limiting Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Cells Genes Genetic Screening Genetic Transcription Genetically Engineered Mouse Goals Human Hyperplasia In Vitro KRAS2 gene Knock-out Laboratories Lung Lung Adenocarcinoma MEKs Malignant Neoplasms Malignant neoplasm of lung Mediating Mitogen-Activated Protein Kinases Modeling Molecular Mouse Cell Line Mus Mutation Normal Cell Normal tissue morphology Oncogenes Oncogenic Outcome Partner in relationship Pathway interactions Patients Phosphorylation Precision therapeutics Protein Family Proteins Ras Inhibitor Ras Signaling Pathway Repression Research Resistance Role Signal Transduction Therapeutic Toxic effect Tumor Tissue Tumorigenicity cancer cell cancer type cell transformation drug discovery experimental study forward genetics in vivo innovation insight lung tumorigenesis member mouse model mutant neoplastic cell new therapeutic target novel overexpression prevent programs receptor small hairpin RNA small molecule inhibitor targeted treatment tumor growth tumorigenesis

项目摘要

ABSTRACT RAS signaling is one of the most commonly altered oncogenic pathways in human cancer and one of the most targeted pathways in drug discovery programs. Yet, while numerous small molecule inhibitors of RAS effectors have been identified, the importance of RAS/MAPK signaling in normal tissues and numerous compensatory signaling mechanisms engaged by cancer cells have prevented their therapeutic utility in many cases. Identifying new therapeutic targets may help overcome the limitations associated with current precision therapies. The goal of this proposal is to define the role of the novel oncogene FAM83B, an important RAS/MAPK intermediary, in driving lung hyperplasia and cancer development in vivo using a newly developed FAM83B mouse model. We originally identified FAM83B in a forward genetic screen for genes that drive human epithelial cell transformation, similar to mutant RAS. Our analysis of FAM83B has generated extensive new information about the molecular functions of FAM83B in cancer cells. We found that elevated FAM83B expression increases RAS/MAPK signaling, resulting in resistance to a number of targeted therapies. Importantly, inhibition of FAM83B suppresses RAS/MAPK signaling and reduces tumor growth. FAM83B is significantly elevated in many cancers, including lung cancer, where it is now recognized as a biomarker in patients with lung adenocarcinoma that have poor outcomes. Here, we propose to use our innovative new FAM83B mouse model to assess how FAM83B contributes to lung tumorigenesis in vivo. The objectives of the proposed studies are to: (i) define the role of FAM83B in driving lung cancer in vivo, alone or in the presence of mutant KRAS, and (ii) determine the FAM83B- dependent molecular changes in MAPK pathway activation responsible for driving tumorigenesis. While the proposed studies focus on FAM83B, the impact of our studies is expected to be considerably broader. A second FAM83 member, FAM83A, was also identified in a forward genetics screen for genes conferring resistance to EGFR TKIs in transformed HMEC. Importantly, FAM83A and FAM83B are members of an 8 member protein family, with all FAM83 proteins now shown to activate MAPK signaling in cancer cell lines (via a highly conserved domain) thereby contributing to tumorigenesis. Thus, our findings using the innovative FAM83B mouse model to assess how FAM83B contributes to MAPK activation and tumorigenesis in vivo will also inform research into all FAM83 members, across numerous cancer types.

抽象的 RAS 信号传导是人类癌症中最常改变的致癌途径之一，也是最常见的致癌途径之一。药物发现计划中的目标途径。然而，虽然无数 RAS效应子的小分子抑制剂已确定 RAS/MAPK 信号传导在正常组织中的重要性以及众多代偿机制在许多情况下，癌细胞参与的信号传导机制阻碍了它们的治疗用途。识别新的治疗靶点可能有助于克服当前精准治疗的局限性。目标该提案的目的是定义新型致癌基因 FAM83B（一种重要的 RAS/MAPK 中介物）在使用新开发的 FAM83B 小鼠模型在体内驱动肺增生和癌症发展。我们最初在驱动人类上皮细胞转化的基因的正向遗传筛选中发现了 FAM83B，与突变型 RAS 类似。我们对 FAM83B 的分析产生了有关该分子的大量新信息 FAM83B 在癌细胞中的功能。我们发现 FAM83B 表达升高会增加 RAS/MAPK 信号传导，导致对许多靶向治疗的耐药性。重要的是，抑制 FAM83B 会抑制 RAS/MAPK 信号传导并减少肿瘤生长。 FAM83B 在许多癌症中显着升高，包括肺癌，现在它被认为是病情较差的肺腺癌患者的生物标志物结果。在这里，我们建议使用我们创新的 FAM83B 小鼠模型来评估 FAM83B 有助于体内肺部肿瘤的发生。拟议研究的目标是： (i) 定义 FAM83B 单独或在突变 KRAS 存在的情况下在体内驱动肺癌，以及 (ii) 确定 FAM83B- MAPK 通路激活的依赖分子变化负责驱动肿瘤发生。虽然拟议的研究重点是 FAM83B，我们的研究的影响预计会更广泛。一秒钟 FAM83 成员 FAM83A 也在正向遗传学筛选中鉴定出赋予抗性的基因转化 HMEC 中的 EGFR TKI。重要的是，FAM83A 和 FAM83B 是 8 成员蛋白的成员家族，所有 FAM83 蛋白现在都被证明可以激活癌细胞系中的 MAPK 信号（通过高度保守的域）从而促进肿瘤发生。因此，我们的研究结果使用创新的 FAM83B 小鼠模型评估 FAM83B 如何促进 MAPK 激活和体内肿瘤发生也将为所有研究提供信息 FAM83 成员，涵盖多种癌症类型。