Synthetic Protein May Work as RAS Inhibitor to Treat Colon and Other Cancers

Synthetic Protein May Work as RAS Inhibitor to Treat Colon and Other Cancers

Nearly 30 percent of all cancers have activating mutations in the RAS family of proteins, but researchers have struggled to safely block these tumor-promoting proteins. But an approach taken by a team at University of Illinois at Chicago may offer a way around this problem.

In the study, “Inhibition of RAS function through targeting an allosteric regulatory site,” published in Nature Chemical Biology, the researchers describe a synthetic binding protein, called NS1 monobody, that can potently inhibit the activity of RAS proteins.

RAS proteins are involved in many aspects of proliferation, development, cell survival, and cell motility. It is not surprising that mutations in these proteins, or in upstream regulators, are often linked to cancer development.

Mutations in the three members of the RAS family — H-RAS, K-RAS, and N-RAS — are present in nearly 30 percent of human tumors. K-RAS mutations are seen in nearly 90 percent of pancreatic cancers, and other RAS mutations are also highly prevalent in colon cancer, melanoma, and lung cancer.

Given their prevalence, researchers have long studied RAS proteins. As a team member said, “development of effective RAS inhibitors represents a ‘holy grail’ in cancer biology.” But to date, scientists have not been able to identify drugs that safely inhibit RAS activity.

Investigators led by John O’Bryan, associate professor of pharmacology in the UIC College of Medicine, used monobody technology to inhibit RAS. Monobodies are high-affinity synthetic proteins that bind to functionally important sites of their respective targets. Unlike conventional antibodies, monobodies are not dependent on the redox potential of their environment, and can be readily used as genetically encoded inhibitors.

“We did not look for a drug or specifically for an inhibitor,” O’Bryan, who is also a member of the University of Illinois Cancer Center, said in a press release. “We used monobody technology, a type of protein-engineering technology, to identify regions of RAS that are critical for its function.”

“The beauty of the technology is that when a monobody binds a protein, it usually works as an inhibitor of that protein,” he added.

Shohei Koide, a study co-author who had already synthesized a pleiotropy of monobodies targeting diverse proteins, developed the NS1 monobody. The researchers found that NS1 bound a region of RAS proteins necessary for them to form activated protein complexes.

Interestingly, the monobody strongly inhibited K-RAS and H-RAS oncogenic activity, but did not influence N-RAS, BRAF, or MEK1 oncogenic activity. This will allow researchers to study the function of RAS proteins in cells, and possibly develop new therapeutic approaches to treat cancer.

“We now have a powerful tool we can use to further probe RAS function,” O’Bryan said. “While future studies and trials are needed before these findings can be leveraged outside the lab, this study provides new insight into how we can potentially inhibit RAS to slow tumor growth.”

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