Identification of lncRNAs Required for Synthetic Lethal Interactions with Mutant KRAS in Pancreatic Cancer
Abstract
This application addresses the Fiscal Year 2017 Peer Reviewed Cancer Research Program Topic Area of pancreatic cancer. The success of this application will benefit pancreatic cancer patients of military Service members, Veterans, and their families. Many factors are known to contribute to the development of pancreatic cancer; one of the important contributing ones is genetic mutations. For example, KRAS mutations account for about 90% pancreatic cancer cases. Thus, researchers have been trying hard to develop drugs against mutant KRAS. However, to date no effective pharmacological inhibitors targeting mutant KRAS have reached the clinic for various reasons. Synthetic lethal approach is a new concept that cancer cells carrying KRAS rely on other genes or pathways to survive. Thus, these genes or pathways serve as potential targets for pancreatic cancer therapy. Our proposed work uses the same concept but with a novel approach to identify long non-coding RNAs involved in synthetic lethal interaction with mutant KRAS in pancreatic cancer. It is well known now that our genome carries two major types of genes. The first type of genes are so-called classic genes, i.e., protein-coding genes, because they can produce proteins that make up our body; the second type of genes are those that do not produce proteins, also called non-coding genes, including long non-coding RNAs and small RNAs such as microRNAs. Although they do not produce proteins, these long non-coding RNAs are very important to protein-coding genes because they can control expression of these protein-coding genes. Amazingly, the number of human long non-coding RNAs is over 50,000 based on updated non-coding RNA databases; this number is even larger than the number of human protein-coding genes (20,000 ~25,000). Thus, long non-coding RNAs are a rich source for biomarker discovery as well as for identification of candidates responsible for synthetic lethal interaction with mutant KRAS in pancreatic cancer. To achieve this goal, we will perform genome-wide screens using our long non-coding RNA knockout and activation libraries. We then functionally characterize candidate long non-coding RNAS identified from the screen and determine how they are involved in synthetic lethal interaction with KRAS in pancreatic cancer. We expect that the success of this study will help identify novel biomarkers and develop a better strategy for pancreatic cancer treatment, thus directly benefiting pancreatic cancer patients of military Service members, Veterans, and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810444
Entities
People
- Yin-Yuan Mo
Organizations
- United States Army
- University of Mississippi