Functional role of the MUC1-C oncoprotein in non-small cell lung cancer

描述(申请人提供)：非小细胞肺癌(NSCLC)，特别是那些携带某些EGFR或K-RAS突变的癌症，通常对分子靶向药物没有反应，预后很差。粘蛋白1(MUC1)是一种在大多数非小细胞肺癌中高表达的跨膜糖蛋白。然而，目前尚不清楚MUC1是否对非小细胞肺癌细胞的生长和存活具有重要作用。在这方面，目前还没有可用的基因工程小鼠模型来研究MUC1参与非小细胞肺癌的启动、进展或维持。MUC1由两个亚基组成：N端胞外粘蛋白亚基(MUC1-N)和C端致癌跨膜亚基(MUC1-C)。MUC1-C胞浆结构域作为EGFR和MET的底物，并与PI3K等与非小细胞肺癌发生相关的效应因子相互作用。在非小细胞肺癌患者中，MUC1-C的过度表达诱导转化和相关的基因标志，这些标志预示着NSCLC患者的无病生存率和总存活率降低。此外，NSCLC细胞中MUC1-C亚单位的抑制与PI3K-&GT；AKT途径的下调和生存的损失有关。拟议工作的总体目标是确定MUC1-C在非小细胞肺癌中的功能作用。我们的假设是，MUC1-C参与了NSCLC的发病过程，并且MUC1-C功能对于带有EGFR和K-RAS突变的NSCLC细胞的生存是必不可少的。这项拟议的工作将在一种新的非小细胞肺癌MUC1-C驱动的小鼠模型中解决这一假设，并通过使用最近开发的MUC1-C抑制剂。MUC1-C是非小细胞肺癌治疗靶点的理论概念是新颖的，可能会改变当前的研究和临床范式。其具体目的是：(1)明确MUC1-C在小鼠非小细胞肺癌发生发展中的作用；(2)评价MUC1-C在伴有EGFR突变的非小细胞肺癌中的作用；(3)确定MUC1-C在K-RAS突变型NSCLC的发生发展中是否起重要作用； 公共卫生相关性：肺癌是美国癌症相关死亡的主要原因。MUC1-C癌蛋白在大多数非小细胞肺癌(NSCLC)细胞中高水平表达。我们的研究集中在MUC1-C在非小细胞肺癌中的功能作用，以及MUC1-C是治疗NSCLC的新靶点的概念。

DESCRIPTION (provided by applicant): Non-small cell lung cancers (NSCLCs), particularly those harboring certain EGFR or K-RAS mutations, are often unresponsive to molecularly targeted agents and have a poor prognosis. Mucin 1 (MUC1) is a transmembrane glycoprotein that is overexpressed in most NSCLCs. However, it is not known if MUC1 is of importance to NSCLC cell growth and survival. In this regard, there are no available genetically-engineered mouse models to study MUC1 involvement in NSCLC initiation, progression or maintenance. MUC1 consists of two subunits~ an N-terminal extracellular mucin subunit (MUC1-N) and a C- terminal oncogenic transmembrane subunit (MUC1-C). The MUC1-C cytoplasmic domain functions as a substrate for EGFR and MET, and interacts with effectors, such as PI3K, that have been linked to NSCLC development. Overexpression of MUC1-C induces transformation and associated gene signatures that are predictive of decreased disease-free and overall survival in NSCLC patients. Moreover, inhibition of the MUC1-C subunit in NSCLC cells is associated with downregulation of the PI3K->AKT pathway and loss of survival. The overall objective of the proposed work is to define the functional role of MUC1-C in NSCLC. Our hypothesis is that MUC1-C contributes to the pathogenesis of NSCLC and that MUC1-C function is essential for survival of NSCLC cells with EGFR and K-RAS mutations. The proposed work will address this hypothesis in a new MUC1-C-driven mouse model of NSCLC and through the use of recently developed MUC1-C inhibitors. The theoretical concept that MUC1-C is a target for the treatment of NSCLC is novel and could shift current research and clinical paradigms. The Specific Aims are: (1) To define involvement of MUC1-C in development of NSCLC in mouse models~ (2) To assess the role of MUC1-C in NSCLC with EGFR mutations~ (3) To determine whether MUC1-C is of importance to development of K-RAS mutant NSCLC~ and (4) To identify how MUC1-C contributes to NSCLC cell survival. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer-related deaths in the United States. The MUC1-C oncoprotein is expressed at high levels in most non-small cell lung cancer (NSCLC) cells. Our proposed research focuses on the functional role of MUC1-C in NSCLC and the concept that MUC1-C is a novel target for the treatment of this disease.