Novel Monobody Could Potentially Inhibit Proteins Prevalent in Cancer

RAS proteins inhibited by the newly created NS1 monobody.

Investigators in a recent study discovered a novel way to block certain genetic mutations found in 30% of cancers.

Mutations in RAS proteins are found in approximately 90% of pancreatic cancers, and are highly prevalent in colon cancer, lung cancer, and melanoma. These RAS proteins include K-RAS, H-RAS, and N-RAS.

The high prevalence of these proteins in cancer, and the tumor’s dependence on the protein for survival, made RAS a heavily studied target for cancer research, according to the study published by Nature Chemical Biology.

Many previous studies have explored the protein in hopes of discovering new treatment options for patients whose cancer is characterized by mutated RAS proteins. However, there has been little success identifying drugs that can safely and effectively inhibit the proteins.

Investigators in the current study took a novel approach, and found that a lab-created synthetic binding protein, called the NS1 monobody, can inhibit the protein family.

“We did not look for a drug or specifically for an inhibitor,” said lead investigator John O’Bryan, PhD. “We used monobody technology, a type of protein-engineering technology, to identify regions of RAS that are critical for its function.”

Monobodies are independent of their environment, unlike antibodies, and can be used as genetically encoded inhibitors, according to the study. These lab-created monobodies have been used to target various proteins, such as enzymes and receptors in previous work.

“The beauty of the technology is that when a monobody binds a protein, it usually works as an inhibitor of that protein,” Dr O’Bryan said.

In the current study, investigators discovered that the NSL monobody is able to bind to a section of the KRAS protein that was not previously known to play an important part in its oncogenetic activity. The monobody was able to block K-RAS and H-RAS by inhibiting the proteins to interact with an identical protein to form a pair, according to the study.

The investigators reported that the NS1 monobody does not appear to have any effect on N-RAS.

These new findings provide important information about how all of the RAS proteins function within the body, specifically in cancer. The investigators believe that this insight may be able to assist the development of novel cancer treatments that inhibit cancerous RAS proteins in cells.

“Development of effective RAS inhibitors represents a ‘holy grail’ in cancer biology,” Dr O’Bryan concluded. “We now have a powerful tool we can use to further probe RAS function. 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.”