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

摘要 RAS信号是人类癌症中最常见的改变的致癌途径之一，也是最常见的 药物发现计划中的有针对性的途径。然而，尽管数量众多 RAS效应器的小分子抑制剂 已经发现，RAS/MAPK信号在正常组织和许多代偿组织中的重要性 癌细胞参与的信号机制在许多情况下阻碍了它们的治疗作用。识别 新的治疗靶点可能有助于克服目前精确治疗的局限性。目标是 这一建议的目的是定义新的癌基因FAM83B，它是一种重要的RAS/MAPK中介，在 使用新开发的FAM83B小鼠模型在体内推动肺增生和癌症的发展。我们 最初在驱动人类上皮细胞转化的基因的正向遗传筛查中发现了FAM83B， 类似于突变的RAS。我们对FAM83B的分析已经产生了关于分子的广泛的新信息 FAM83B在癌细胞中的功能我们发现FAM83B的高表达增加了RAS/MAPK 信号传递，导致对一些靶向治疗产生抵抗。重要的是，抑制FAM83B可以抑制 RAS/MAPK信号转导和抑制肿瘤生长。FAM83B在许多癌症中显著升高，包括 肺癌，现在被认为是肺腺癌患者的一个生物标记物 结果。在这里，我们建议使用我们创新的新FAM83B鼠标模型来评估FAM83B如何 在体内对肺肿瘤的发生有贡献。拟议研究的目标是：(1)界定 FAM83B在体内、单独或在突变KRAS存在下驱动肺癌的作用，以及(Ii)确定FAM83B- MAPK通路激活依赖的分子变化导致肿瘤的发生。而当 拟议的研究集中在FAM83B上，我们的研究的影响预计将相当广泛。一秒钟 FAM83成员FAM83A也在正向遗传学筛查中被发现，以寻找与抗病有关的基因 转化的HMEC中存在EGFR TKI。重要的是，FAM83A和FAM83B是8个成员蛋白质的成员 FAM83蛋白家族，现在发现所有的FAM83蛋白都能激活癌细胞系中的MAPK信号(通过高度保守的 领域)，从而促进肿瘤的发生。因此，我们的发现使用创新的FAM83B小鼠模型来 评估FAM83B如何在体内促进MAPK激活和肿瘤形成也将为ALL的研究提供信息 FAM83成员，涉及多种癌症类型。

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.