Credit: John P. O’Bryan, et al. Published in Nature Chemical Biology.
Researchers at the University of Illinois at Chicago have identified a new way to block the action of genetic mutations found in nearly 30 percent of all cancers.
Mutations in genes for the RAS family of proteins are present in nearly 90 percent of pancreatic cancers and are also highly prevalent in colon cancer, lung cancer and melanoma, the most dangerous kind of skin cancer.
The group of proteins include three members, K-RAS, H-RAS and N-RAS.
The prevalence of RAS mutations in human cancers and the dependence of tumors on RAS for survival has made a RAS a prime target for cancer research and drug discovery. Scientists and drug developers have long studied RAS oncogenes hoping to find a new treatment for cancer, but they have not yet been able to identify drugs that safely inhibit the oncogene’s activity.
John O’Bryan, associate professor of pharmacology in the UIC College of Medicine, led a team of researchers that took a different approach to studying RAS, and discovered that a synthetic binding protein they call “NS1 monobody,” which they created in the lab, can block the activity of the RAS proteins.
Unlike conventional antibodies, monobodies are not dependent on their environment and can be readily used as genetically encoded inhibitors.
Monobodies were developed by Shohei Koide, a co-author on the study who is professor of biochemistry and molecular pharmacology at New York University. They have been used to target a diverse array of proteins that include enzymes and receptors.
The researchers found that the NS1 monobody binds to an area of the RAS protein molecule that was not previously known to be important for its oncogenic activity. NS1 strongly inhibits oncogenic K-RAS and H-RAS function by blocking the ability of the protein to interact with an identical one to form a molecular pair. NS1 does not affect N-RAS.
This study was supported in part by a Catalyst award from the Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust to O’Bryan and Koide, with additional funding from the Department of Veterans Affairs and the National Institutes of Health.