Defining the role of FAM83A in Herceptin-resistant breast cancer

 描述(申请人提供)：HER2阳性乳腺癌(HER2+BC)是一种侵袭性亚型，预后较差。尽管针对HER2受体的单抗Herceptin提高了HER2+BC患者的存活率，但许多患者存在从头开始的Herceptin耐药性。此外，大多数最初对赫赛汀治疗有反应的患者最终会产生耐药性。为了克服从头治疗和获得性赫赛汀耐药的破坏性影响，必须确定新的治疗靶点。本提案的目的是确定新的癌基因FAM83A(对于具有序列相似性83的家族，成员A)如何驱动Herceptin耐药性，并确定FAM83A可能是如何靶向克服耐药性的。FAM83A在HER2+BCS中高表达，尤其是Herceptin耐药细胞。事实上，对Herceptin抗性的选择会导致FAM83A表达显著增加。重要的是，抑制FAM83A抑制了Herceptin耐药细胞的增殖，关闭了下游效应信号，并使细胞对Herceptin重新敏感。综上所述，我们的初步研究表明，FAM83A是Herceptin耐药细胞中的关键信号成分，并提供了靶向FAM83A可能具有临床益处的原理证据。我们提出的研究的短期目标是更好地理解FAM83A促进Herceptin耐药HER2信号的分子机制。拟议研究产生的结果将对我们以FAM83A介导的信号复合体形成为治疗靶点的长期目标至关重要。为了明确FAM83A在赫赛汀耐药中的作用，提出了两个特定的目标。在目标1中，我们将确定FAM83A升高如何在Herceptin耐药BC中对过度活跃的受体激活信号起作用。通过在体外实验中操纵一组Herceptin敏感和耐药癌细胞以及体内患者来源的肿瘤细胞中FAM83A的水平，我们建议定义这种新癌基因的高水平如何改变HER2的激活状态、下游效应信号和HER2沉积基因表达特征。在目标2中，我们将鉴定FAM83A带到HER2受体促进Herceptin耐药HER2信号转导的关键蛋白，并开始询问它们在Herceptin耐药中的作用。拟议研究的完成将提供对FAM83A如何调节介导赫赛汀耐药性的复杂信号级联反应的更清晰的理解。明确FAM83A在调节促进Herceptin耐药性的信号复合体中的作用将有助于更好地理解HER2驱动的肿瘤发生和靶向治疗耐药性。我们从拟议的研究中获得的见解将为靶向FAM83A介导的信号过度激活奠定基础，使我们更接近于克服赫赛汀耐药性的破坏性影响。

 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.