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）是一种预后不良的侵袭性亚型。尽管靶向HER2受体的单克隆抗体赫赛汀改善了HER2+ BC患者的生存率，但许多患者存在新发赫赛汀耐药。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。该提案的目的是定义新癌基因FAM83A（对于具有序列相似性83的FAMily，成员A）如何驱动赫赛汀耐药性，并确定如何靶向FAM83A以克服耐药性。FAM83A在HER2+ BC中过表达，特别是赫赛汀耐药细胞。事实上，赫赛汀抗性的选择导致FAM83A表达的显著增加。重要的是，FAM83A的抑制抑制赫赛汀抗性细胞增殖，关闭下游效应信号传导，并使细胞对赫赛汀重新敏感。综上所述，我们的初步研究表明FAM83A是赫赛汀耐药细胞中的关键信号传导组分，并提供了靶向FAM83A可能具有临床益处的原理证明。我们提出的研究的短期目标是更好地理解FAM83A促进赫赛汀耐药HER2信号传导的分子机制。从所提出的研究中产生的结果对于我们治疗靶向FAM83A介导的信号传导复合物形成的长期目标至关重要。为了确定FAM83A在赫赛汀耐药性中的作用，提出了两个具体目标。在目标1中，我们将确定升高的FAM83A如何在赫赛汀耐药BC中促进过度活跃的受体激活信号传导。通过实验操纵FAM83A水平在一组赫赛汀敏感和赫赛汀耐药的癌细胞在体外和患者源性肿瘤在体内，我们建议确定如何升高水平的这种新的癌基因改变HER2的激活状态，下游效应信号，和HER2 depoendent基因表达的签名。在目标2中，我们将鉴定FAM83 A带给HER2受体以促进赫赛汀耐药HER2信号传导的关键蛋白，并开始探究它们在赫赛汀耐药中的作用。完成拟议的研究将更清楚地了解FAM83A如何调节介导赫赛汀耐药的复杂信号级联。确定FAM83A在调节促进赫赛汀耐药的信号复合物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。从我们提出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.