KRAS is a major oncogene for pancreatic (>90%), colorectal (>40%), and lung cancers (>16%); three cancer types that are responsible for 23% of cancer incidence and 43% cancer. Naturally, concerted efforts have focused on developing therapies against oncogenic KRAS- inhibition of KRAS expression, membrane association, effector signaling pathways, etc. However, success has been limited over the past 30 years. Although these past strategies have failed for diverse reasons, one commonality is that they target both the wild-type (WT) and oncogenic forms of KRAS. Our recent publication reported that increased loss of the WT-KRAS allele in the presence of oncogenic KRAS is associated with pancreatic cancer metastasis in both human samples and mouse modeling. We have also demonstrated that restoration of WT-KRAS expression in pancreatic cancer cells reduced cancer cell invasiveness in vitro and in vivo. These findings challenge the canonical view of KRAS functions and prompted us to hypothesize that the WT- KRAS may serve as a tumor-suppressor gene in metastasis in the presence of mutant KRAS. To-date, little attention has been bestowed on the function of WT-KRAS in the context of cancer. To test our hypothesis, in Aim 1, we will investigate if the loss of the WT-Kras allele in pancreatic cancer cells with mutant Kras would increase tumor burden and/or metastasis in vivo.
In Aim 2, we will investigate if the restoration of WT-Kras expression will suppress pancreatic tumor progression and metastasis in vivo.
Aim 3, we will generate differential molecular profiles between pancreatic cancer cells with Krasmt/wt and Krasmt/- genotypes and investigate the translational values of these differentially expression genes. The innovations here include: 1) We will employ in vivo multi-fluorescence labeling systems to differentially label pancreatic cancer cells that possess mutant Kras with or without WT-Kras. We will trace these differentially fluorescence-labeled cancer cells in mice as the tumors progress to metastasis, in both visual and quantitative manners. 2) The complementary designs of Aim 1 and Aim 2 (to evaluate the loss or restoration of WT-Kras on tumor progression and metastasis in vivo) will stringently test our hypothesis that the WT-Kras is involved in metastasis. 3) Finally, the identification of differentially expressed genes in Aim 3 wll not only provide the molecular mechanisms for the observed phenotypic differences between Krasmt/wt and Krasmt/- pancreatic cancer cells, but also potential prognostic markers and new gene targets for the next generation of KRAS target therapies that will distinguish between WT and mutant KRAS signaling. Although we cannot be certain that the ability for a new therapeutic to discriminate between WT and mutant KRAS will be the panacea for KRAS target therapies. Nevertheless, the potential role of WT-KRAS in cancer metastasis has to be addressed and may have profound impacts on future cancer research and patient care.

Public Health Relevance

Our recent data showed that increased loss of the wild-type KRAS allele in the presence of oncogenic KRAS is associated with pancreatic cancer metastasis. Here we propose to investigate our hypothesis in vivo that the wild-type KRAS acts as a tumor-suppressor in the presence of activated KRAS, and the obliteration of the wild-type KRAS allele in pancreatic tumor cells may offer growth advantages to cancer cells and promote metastasis. The success of this project has pertinent implications on the development of future KRAS target therapies and profound impacts on patient care for pancreatic, colon, and lung cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA178445-01A1
Application #
8913459
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Snyderwine, Elizabeth G
Project Start
2015-05-01
Project End
2020-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032