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

描述（由申请人提供）：非小细胞肺癌（nsclc），特别是那些携带某些EGFR或K-RAS突变的肺癌，通常对分子靶向药物无反应，预后较差。Mucin 1 （MUC1）是一种跨膜糖蛋白，在大多数非小细胞肺癌中过表达。然而，MUC1是否对NSCLC细胞生长和存活具有重要意义尚不清楚。在这方面，没有可用的基因工程小鼠模型来研究MUC1参与NSCLC的发生、进展或维持。MUC1由两个亚基组成：n端细胞外粘蛋白亚基（MUC1- n）和C端致癌跨膜亚基（MUC1-C）。MUC1-C细胞质结构域作为EGFR和MET的底物，并与PI3K等效应物相互作用，这些效应物与NSCLC的发展有关。MUC1-C过表达诱导转化和相关基因特征，预测非小细胞肺癌患者无病生存率和总生存率降低。此外，在NSCLC细胞中，MUC1-C亚基的抑制与PI3K->AKT通路的下调和生存期的丧失有关。本研究的总体目标是明确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的发病机制，MUC1-C的功能对于EGFR和K-RAS突变的NSCLC细胞的存活至关重要。这项工作将通过使用最近开发的MUC1-C抑制剂，在新的MUC1-C驱动的非小细胞肺癌小鼠模型中解决这一假设。MUC1-C是治疗非小细胞肺癌的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例。具体目的是：(1)明确MUC1-C在小鼠模型中参与NSCLC的发展~(2)评估MUC1-C在EGFR突变的NSCLC中的作用~(3)确定MUC1-C在K-RAS突变的NSCLC的发展中是否重要~(4)确定MUC1-C对NSCLC细胞存活的影响。

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.