How to inhibit oncogenes
Researchers at the University of Illinois at Chicago, working under the guidance of Associate Professor John O'Brien, have identified a new mechanism for blocking the action of mutations found in almost 30% of cancer cells.
Mutations of RAS family genes, including three genes K-RAS, H-RAS and N-RAS, are detected in pancreatic cancer cells in almost 90% of cases. They are also often found in colon cancer cells, lungs and melanomas – the most dangerous malignant skin tumors.
The prevalence of RAS family gene mutations in human malignant tumors, as well as the dependence of tumors on these mutations, have made them an important target of cancer research and drug development. Specialists in these fields have been studying oncogenes of the RAS family for a long time in the hope of finding new ways to treat cancer, but so far they have not been able to find compounds that inhibit the activity of oncogenes without harming the body.
The authors applied an alternative approach to the study of RAS mutations and demonstrated that the synthetic binding protein synthesized by them, called "NS1 monotelo", successfully copes with this task. According to O'Brien, they did not search for a drug that has an inhibitory effect, but used a kind of protein engineering, known as the monotel technology, to identify regions of the RAS family genes that are critical for performing the functions of their protein products.
Unlike traditional antibodies, monotheles are independent of the environment and can be used as genetically encoded inhibitors. O'Brien notes that the beauty of this technology is that if a monotelo binds to a protein, it usually works as an inhibitor of that protein. Monotheles developed by one of the authors of the study, Professor Shohei Koide, are used to target a wide range of proteins, including a variety of enzymes and receptors.
The authors found that NS1-monotelo binds to a region of the RAS protein molecule that was not previously considered important for oncogenic activity. NS1 has a strong inhibitory effect on the functions of RAS and H-RAS by blocking the ability of these proteins to interact with a second identical protein molecule and form a molecular pair. However, it has no effect on N-RAS.
Figure from an article in Nature Chemical Biology
O'Brien notes that the data obtained provide important information about the long-standing mystery of the function of RAS family proteins in the cell. This information can help in the development of new therapeutic approaches to cancer treatment by influencing the functions of mutant variants of these proteins in cancer cells. The development of effective RAS inhibitors is the "holy grail" of cancer biology and now researchers have at their disposal a powerful new tool that can be used to further study the functions of this family of proteins. While further research and clinical trials are necessary to bring the new approach to the clinical level, the first demonstration of its effectiveness indicates to us the potential of inhibiting RAS proteins to slow down tumor growth.
Article by Russell Spencer-Smith et al. Inhibition of RAS function through targeting an allosteric regulatory site is published in the journal Nature Chemical Biology.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the University of Illinois: UIC researchers discover a way to inhibit major cancer gene.
14.11.2016