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

• 批准号: 10201807
• 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
• 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/10201807
• 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

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见的致癌途径之一，也是最常见的途径之一 药物发现计划中的有针对性途径。但是，虽然很多 RAS效应子的小分子抑制剂 已经确定了RAS/MAPK信号在正常组织中的重要性和许多代偿性 在许多情况下，癌细胞参与的信号传导机制已阻止其治疗效用。识别 新的治疗靶标可能有助于克服与​​当前精确疗法相关的局限性。目标 该提议的内容是定义新颖的Oncogene Fam83b（重要的RAS/MAPK中介）的作用 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鉴定了FAM83B， 类似于突变的Ras。我们对FAM83B的分析产生了有关分子的广泛新信息 FAM83B在癌细胞中的功能。我们发现升高的FAM83B表达增加了RAS/MAPK 信号，导致对多种靶向疗法的抗性。重要的是，抑制FAM83B抑制 RAS/MAPK信号传导并减少肿瘤的生长。 FAM83B在许多癌症中都显着升高 肺癌，现在被认为是肺腺癌患者的生物标志物 结果。在这里，我们建议使用创新的新FAM83B鼠标模型来评估FAM83B的方式 在体内有助于肺肿瘤发生。拟议研究的目标是：（i）定义 FAM83B在体内驱动肺癌中，单独或在存在突变kras的情况下，以及（ii）确定FAM83B-- MAPK途径激活的依赖分子变化负责驱动肿瘤发生。而 拟议的研究重点是FAM83B，我们的研究的影响预计将更广泛。第二 FAM83成员FAM83A在向前遗传学屏幕中也被鉴定出来，以赋予对抗性的基因 转换的HMEC中的EGFR TKI。重要的是，FAM83A和FAM83B是8个成员蛋白的成员 家族，所有FAM83蛋白现在都显示出来激活癌细胞系中的MAPK信号传导（通过高度保守 域），从而导致肿瘤发生。因此，我们使用创新的FAM83B鼠标模型的发现 评估FAM83B如何促进MAPK激活和体内肿瘤发生也将为所有人提供研究 FAM83成员，多种癌症类型。