Approximately 25% of all tumor types sustain oncogenic RAS mutations. Oncogenic RAS activation confers multiple tumor-promoting characteristics including unrestrained proliferation, survival signaling, and increased invasiveness. These features are mediated by oncogene-induced reactive oxygen species (ROS). However oncogenic ROS also lead to DNA damage, which is a major effector of cell death and cell senescence, two common therapeutic outcomes. Hence, RAS-transformed cells must evade ROS- associated damaging effects without entirely eliminating ROS production. Studies have shown that proteins that can effectively suppress ROS-associated anti-tumorigenic functions promote RAS-mediated tumor formation. The mammalian 8-oxo-dGTP triphosphatase, human MutT Homolog 1(MTH1) is unique in that its functionality inhibits oxidative DNA damage but does not directly affect ROS levels. Studies from our laboratory as well as others indicate unusually high expression of MTH1 in cancers associated with activating RAS mutations. Our published and preliminary data further show that oncogenic RAS expression upregulates MTH1 protein levels in a number of different cell types. We also recently reported MTH1 overexpression in normal cells prevents oncogenic RAS-induced oxidative DNA damage and cellular senescence, a critical barrier against oncogene-induced tumorigenesis. Conversely, we found MTH1 suppression selectively affects proliferation and survival pathways in the RAS-transformed counterparts in isogenic breast cancer cell lines. Our preliminary data further indicate that MTH1 suppression affects transformation efficiency, xenograft tumor formation, pro-survival pathways and invasive morphology in oncogenic RAS-transformed cells. Thus our central hypothesis is that elevated MTH1 expression is a critical adaptive change that functionally uncouples the tumor-promoting effects of oncogenic ROS from their damaging effects, thus enhancing proliferation and survival of RAS-transformed cells. The overall goal of this proposal is: 1) to fully characterize the molecular and cellular implications of MTH1 upregulation on oncogenic RAS-induced mechanisms of tumor development and promotion, and 2) to assess the in vivo effects of abrogating MTH1 function in an activated KRAS mouse model of lung cancer. Our studies will provide mechanistic validation for targeting MTH1 in RAS-transformed tumors as a means to enhance therapeutic efficacy by shifting cellular response away from pro-proliferative and pro-survival mechanisms and towards cell senescence or cell death.

Public Health Relevance

Approximately 25% of all tumors sustain activating mutations in the RAS oncogene, resulting in aggressive and treatment-resistant malignancies. Our proposed studies will characterize novel molecular mechanisms by which RAS-transformed tumors evade chronic oncogenic signaling-generated oxidative stress and resulting tumor-suppressive outcomes. Understanding these mechanisms is critical for developing effective chemotherapeutic approaches against oncogenic RAS-sustaining cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA175086-02
Application #
8657017
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Watson, Joanna M
Project Start
2013-05-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$308,958
Indirect Cost
$107,683
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Patel, A; Burton, D G A; Halvorsen, K et al. (2015) MutT Homolog 1 (MTH1) maintains multiple KRAS-driven pro-malignant pathways. Oncogene 34:2586-96