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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA166480-02
Application #
8446331
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Salnikow, Konstantin
Project Start
2012-04-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$502,149
Indirect Cost
$190,897
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Rowbotham, S P; Li, F; Dost, A F M et al. (2018) H3K9 methyltransferases and demethylases control lung tumor-propagating cells and lung cancer progression. Nat Commun 9:4559
Maeda, Takahiro; Hiraki, Masayuki; Jin, Caining et al. (2018) MUC1-C Induces PD-L1 and Immune Evasion in Triple-Negative Breast Cancer. Cancer Res 78:205-215
Rajabi, Hasan; Hiraki, Masayuki; Kufe, Donald (2018) MUC1-C activates polycomb repressive complexes and downregulates tumor suppressor genes in human cancer cells. Oncogene 37:2079-2088
Deng, Jiehui; Wang, Eric S; Jenkins, Russell W et al. (2018) CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation. Cancer Discov 8:216-233
Panchamoorthy, Govind; Jin, Caining; Raina, Deepak et al. (2018) Targeting the human MUC1-C oncoprotein with an antibody-drug conjugate. JCI Insight 3:
CaƱadas, Israel; Thummalapalli, Rohit; Kim, Jong Wook et al. (2018) Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Nat Med 24:1143-1150
Stroopinsky, Dina; Rajabi, Hasan; Nahas, Myrna et al. (2018) MUC1-C drives myeloid leukaemogenesis and resistance to treatment by a survivin-mediated mechanism. J Cell Mol Med :
Rusan, Maria; Li, Kapsok; Li, Yvonne et al. (2018) Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression. Cancer Discov 8:59-73
Hiraki, Masayuki; Maeda, Takahiro; Mehrotra, Neha et al. (2018) Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer. Signal Transduct Target Ther 3:13
Gupta, Dikshi; Kumar, Manoj; Tyagi, Priyanka et al. (2018) Concomitant Delivery of Paclitaxel and NuBCP-9 peptide for synergistic enhancement of cancer therapy. Nanomedicine 14:1301-1313

Showing the most recent 10 out of 140 publications