Oncogenic mutations in Ras proteins lead to transforming potential in a number of epithelial cells. Unfortunately, the ability to suppress the Ras-driven signaling pathway in tumors, to date, has largely been unsuccessful. We originally showed that the transcription factor NF-?B is important for Ras-induced cell transformation through its ability to suppress Ras-induced cell death. In the first in vivo test for a role of NF-?B in oncogene-induced tumorigenesis, we show here that loss of the gene encoding the RelA/p65 NF-?B subunit suppresses Ras-induced tumorigenesis in a lung tumor model. Importantly, loss of RelA/p65 leads to apoptosis in these Ras-transformed cells. In vitro data indicate that IKKa and ?, upstream regulators of NF-?B, and Aurora kinase control the ability of oncogenic Ras mutants to activate NF-?B. Additional new data indicate that variant forms of IKK, namely TBK1 and IKKe, nuclear in human lung tumor cells and that a dominant negative form of IKKe blocks NF-kB activation in these cells. Work from Counter and colleagues shows that the PI3K/Akt pathway is critical for tumor maintenance in a Ras-induced setting. We provide preliminary data that IKKa, in a manner distinct from its ability to control NF-?B activation, promotes Akt activity in cancer cells through regulation of the TORC2 complex. Due to the poor prognosis of many lung cancer patients and the hope for improved therapy of lung cancer, we have focused this proposal on K-Ras-induced lung tumorigenesis. The central hypotheses of this application are that: (1) a critical downstream effector of oncogenic K-Ras in lung cancer is the transcription factor NF-?B, (2) NF-?B activation induced by K-Ras involves therapeutic targets: Aurora kinases and I?B kinase a and ? (IKK?), and potentially TBK1/IKKe and GSK-a/?;(3) therapies targeting IKK or Aurora kinase, and potentially GSK-a/? will suppress tumor growth.
Four specific aims are proposed to test these hypotheses. The proposed research may provide an experimental foundation leading to new treatments for Ras-positive tumors and will provide insight into molecular signaling events that are dysregulated downstream of mutant Ras expression.

Public Health Relevance

While transforming mutations in Ras proteins occur widely in a number of cancers, the ability to suppress the pro-oncogenic effects of these proteins has largely failed. We originally showed that the transcription factor NF-?B is important for the ability of oncogenic to Ras to efficiently transform cells. Here we explore the importance of the NF-?B and IKK proteins in controlling K- Ras-induced lung tumorigenesis and lung tumor maintenance, using both genetically engineered animal models and pharmacologic inhibitors. In parallel, we explore molecular mechanisms whereby NF-?B and IKK function to promote oncogenic conversion and tumor maintenance. The proposed experiments have the potential to identify new targetable signaling pathways for treatment of Ras-expressing tumors, including those of the lung.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073756-13
Application #
8207265
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Watson, Joanna M
Project Start
1998-08-15
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
13
Fiscal Year
2012
Total Cost
$252,369
Indirect Cost
$81,850
Name
University of North Carolina Chapel Hill
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Dan, Han C; Ebbs, Aaron; Pasparakis, Manolis et al. (2014) Akt-dependent activation of mTORC1 complex involves phosphorylation of mTOR (mammalian target of rapamycin) by I?B kinase ? (IKK?). J Biol Chem 289:25227-40
Kendellen, M F; Bradford, J W; Lawrence, C L et al. (2014) Canonical and non-canonical NF-*B signaling promotes breast cancer tumor-initiating cells. Oncogene 33:1297-305
Bradford, Jennifer W; Baldwin, Albert S (2014) IKK/nuclear factor-kappaB and oncogenesis: roles in tumor-initiating cells and in the tumor microenvironment. Adv Cancer Res 121:125-45
Bang, Deepali; Wilson, Willie; Ryan, Meagan et al. (2013) GSK-3* promotes oncogenic KRAS function in pancreatic cancer via TAK1-TAB stabilization and regulation of noncanonical NF-*B. Cancer Discov 3:690-703
Cooper, Matthew J; Cox, Nathan J; Zimmerman, Eric I et al. (2013) Application of multiplexed kinase inhibitor beads to study kinome adaptations in drug-resistant leukemia. PLoS One 8:e66755
Hutti, Jessica E; Pfefferle, Adam D; Russell, Sean C et al. (2012) Oncogenic PI3K mutations lead to NF-ýýB-dependent cytokine expression following growth factor deprivation. Cancer Res 72:3260-9
Comb, William C; Hutti, Jessica E; Cogswell, Patricia et al. (2012) p85ýý SH2 domain phosphorylation by IKK promotes feedback inhibition of PI3K and Akt in response to cellular starvation. Mol Cell 45:719-30
Comb, W C; Cogswell, P; Sitcheran, R et al. (2011) IKK-dependent, NF-?B-independent control of autophagic gene expression. Oncogene 30:1727-32
Stein, S J; Baldwin, A S (2011) NF-ýýB suppresses ROS levels in BCR-ABL(+) cells to prevent activation of JNK and cell death. Oncogene 30:4557-66
Basseres, Daniela S; Ebbs, Aaron; Levantini, Elena et al. (2010) Requirement of the NF-kappaB subunit p65/RelA for K-Ras-induced lung tumorigenesis. Cancer Res 70:3537-46

Showing the most recent 10 out of 44 publications