Defining the role of FAM83A in Herceptin-resistant breast cancer

定义 FAM83A 在赫赛汀耐药乳腺癌中的作用

• 批准号: 9022860
• 负责人: MARK W. JACKSON
• 金额: $ 17.24万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-08 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9022860
• 关键词: Ablation; Age; Biochemical; Biological; Cell Line; Cell Proliferation; Cells; Clinical; Clinical Management; Complex; Data; Development; Diagnosis; ERBB2 gene; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Family; Foundations; Future; Gene Expression Profile; Goals; Growth; In Vitro; Laboratories; Left; MAP Kinase Gene; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Monoclonal Antibodies; Oncogenes; PI3K/AKT; Patients; Phosphorylation; Proteins; Receptor Protein-Tyrosine Kinases; Refractory; Resistance; Resistance development; Role; Signal Transduction; Survival Rate; Time; Trastuzumab; Tumor-Derived; Tumorigenicity; Woman; base; cancer cell; combat; fight against; genetic signature; improved; in vivo; indium arsenide; insight; malignant breast neoplasm; member; new therapeutic target; novel; novel therapeutics; outcome forecast; overexpression; public health relevance; receptor; response; small hairpin RNA; targeted treatment; tumorigenesis; young adult

 DESCRIPTION (provided by applicant): HER2-positive breast cancer (HER2+ BC) is an aggressive subtype with a poor prognosis. Although the monoclonal antibody Herceptin, which targets the HER2 receptor, has improved survival rates in patients with HER2+ BC, many patients present with de novo Herceptin resistance. Furthermore, the majority of patients that initially respond to Herceptin treatment will ultimately develop resistance. To overcome the devastating effects of de novo and acquired Herceptin resistance, new therapeutic targets must be identified. The purpose of this proposal is to define how the novel oncogene FAM83A (for FAMily with sequence similarity 83, member A), drives Herceptin resistance and to determine how FAM83A might be targeted to overcome resistance. FAM83A is overexpressed in HER2+ BCs, particularly Herceptin-resistant cells. In fact, selection for Herceptin resistance results ina significant increase in FAM83A expression. Importantly, inhibition of FAM83A represses Herceptin-resistant cell proliferation, turns off downstream effector signaling, and re-sensitizes cells to Herceptin. Taken together, our preliminary studies implicate FAM83A is key signaling component in Herceptin resistant cells and provide a proof-of-principle that targeting FAM83A may have clinical benefit. The short-term goal of our proposed studies is to provide a greater understanding of the molecular mechanism by which FAM83A promotes Herceptin-resistant HER2 signaling. The results generated from the proposed studies will be critical for our long-term goal of therapeutically targeting FAM83A-mediated signaling complex formation. To define the role of FAM83A in Herceptin resistance, two specific aims are proposed. In Aim 1, we will determine how elevated FAM83A contributes to hyperactive receptor-activated signaling in Herceptin resistant BC. By experimentally manipulating FAM83A levels in a panel of Herceptin-sensitive and Herceptin-resistant cancer cells in vitro and patient-derived tumors in vivo, we propose to define how elevated levels of this novel oncogene alter the activation status of HER2, downstream effector signaling, and HER2-depoendent gene expression signatures. In Aim 2, we will identify key proteins that FAM83A brings to the HER2 receptor to promote Herceptin-resistant HER2 signaling and begin to interrogate their role in Herceptin resistance. Completion of the proposed studies will provide a clearer understanding of how FAM83A regulates the complex signaling cascades that mediate Herceptin resistance. Defining the role of FAM83A in modulating the signaling complexes that promote Herceptin resistance will provide a greater understanding of HER2-driven tumorigenesis and targeted therapy resistance. The insight gained from our proposed studies will lay the foundation for targeting FAM83A-mediated signaling hyperactivation, bringing us closer to overcoming the devastating effects of Herceptin resistance.

 描述（由适用提供）：HER2阳性乳腺癌（HER2+ BC）是一种侵略性亚型，预后不良。尽管靶向HER2受体的单克隆抗体赫斯蒂蛋白在HER2+ BC患者中的存活率提高了，但许多患者均具有从头赫斯蒂蛋白的耐药性。此外，最初对赫赛汀治疗反应的大多数患者最终会发展出抗药性。为了克服从头开始的毁灭性影响并获得了赫赛汀的抵抗，必须确定新的治疗靶标。该提议的目的是定义新型的癌基因FAM83A（对于具有序列相似性的家族83，成员A）如何驱动赫赛汀的抵抗力，并确定如何将FAM83A靶向克服抵抗力。 FAM83A在HER2+ BC中过表达，尤其是抗赫赛抗素的细胞。实际上，选择赫赛汀耐药性会导致FAM83A表达的显着增加。重要的是，对FAM83A的抑制反映了抗赫斯蒂蛋白的细胞增殖，关闭下游效应子信号传导以及对赫赛汀的重新敏感细胞。综上所述，我们的初步研究暗示FAM83A是耐药细胞中的关键信号传导成分，并提供了瞄准FAM83A可能具有临床益处的原则证明。我们提出的研究的短期目标是对FAM83A促进抗赫斯蒂蛋白耐药的HER2信号传导的分子机制有更深入的了解。根据提出的研究产生的结果对于我们的长期靶向FAM83A介导的信号传导复合物的形成至关重要。为了定义FAM83A在赫赛汀抵抗中的作用，提出了两个具体的目标。在AIM 1中，我们将确定FAM83A的升高是如何促进赫赛普抗蛋白耐药性BC中过度活跃的受体激活信号传导的。通过在体外在体外和患者衍生的肿瘤中对FAM83A水平进行实验操纵FAM83A水平，我们建议定义这种新颖的致癌基因升高的水平如何改变HER2的激活状态，下游效应器信号传导和Her2依赖性基因依赖性基因依赖性基因依赖性依赖性基因依赖性基因。在AIM 2中，我们将确定FAM83A带给HER2受体的关键蛋白质，以促进抗赫斯蒂蛋白的HER2信号，并开始审问其在赫赛普毒素抵抗中的作用。拟议的研究的完成将对FAM83A如何调节介导赫赛门抵抗的复杂信号级联反应提供更清晰的了解。定义FAM83A在调节促进赫赛汀耐药性的信号传导复合物中的作用将提供对HER2驱动的肿瘤发生和靶向治疗耐药性的更多了解。从我们提出的研究中获得的洞察力将奠定针对FAM83A介导的信号传导过度激活的基础，从而使我们更加紧密克服了赫赛汀抵抗的毁灭性影响。