As a 10-year journey comes to fruition, MUSC Hollings Cancer Center researcher John O’Bryan, Ph.D., and his colleagues have demonstrated a new therapeutic method to block a protein that is frequently mutated in cancers. These proof-of-principle results were published Feb. 8 in Cell Reports. This work, which involves inhibiting the oncogenic protein RAS using small molecules, provides a solid basis for the development of clinical cancer therapies.
The American Cancer Society estimates that 1.9 million new cases of cancer will be diagnosed this year. Based on the urgent need for more effective therapies, researchers are always on the hunt for elusive treatments that can affect many cancers.
O’Bryan, who is a professor in the Department of Cellular and Molecular Pharmacology and Experimental Therapeutics at the Medical University of South Carolina, said: “The RAS is one of the most central and critical regulators of proliferation cellular, and it is also the most mutated in cancers. The mutated RAS leads to the growth of tumors. This makes it an attractive therapeutic target.
The RAS protein family is mutated in nearly 20% of human tumors; however, there has been little progress in drug development for this target. “Think of RAS as a smooth bullet that doesn’t let anything bind to it. Until recently it was thought that mutant RAS couldn’t be targeted with drugs. Now there is an FDA-approved drug for mutant RAS in lung cancer, demonstrating that it is possible to target mutant RAS in some cases,” O’Bryan said.
The new drug sotorasib targets a mutant form of RAS that only occurs in less than 3% of all human cancers, so the new drug isn’t very useful for several types of cancers, O’Bryan said. His new method of therapeutically targeting mutant RAS is more promising because it has the potential to work with many mutant forms of RAS in multiple cancers.
“Pancreas, lung and colorectal cancers are three of the four deadliest cancers, and their growth is driven by mutations in RAS proteins. Therefore, successfully targeting mutant RAS has great implications for patients,” O’Bryan said.
The challenge with RAS targeting is the way it works. It has “on” and “off” states which are regulated by binding to other molecules called nucleotides. There is also a third state called the nucleotide-free state when it switches between on and off modes. However, RAS proteins are in their nucleotide-free state for such a short time that it was previously thought that RAS could not be targeted during this very short-lived state.
O’Bryan’s collaborator, Shohei Koide, Ph.D., of New York University’s Perlmutter Cancer Center, developed the one-body technology that overcomes the challenges of targeting RAS without a nucleotide. Monobodies are small, synthetic binding proteins that can be engineered to attach to cellular targets inside or outside cells. Previously, targeting nucleotide-less RAS mutants was considered an impossible undertaking.
Targeting nucleotide-free RAS with the R15 monobody has allowed researchers to better understand the biochemistry of RAS and uncover opportunities to disrupt its anti-cancer activity. Using a mixture of biochemical techniques, cell culture work and animal models, they found that the R15 unibody blocks several forms of RAS mutants.
“We were surprised to find that many RAS mutants unlock nucleotides and that the R15 unibody can block them,” O’Bryan said. “It is a good sign that more than 50% of oncogenic RAS mutants may be susceptible to non-nucleotide RAS-binding inhibitors. This makes nucleotide-free RAS targeting a viable approach to inhibit many RAS-induced mutant tumors.
There is often serendipity in a research career, O’Bryan said. “We were stuck with our first data because it didn’t make immediate sense. However, it turned out to be an exciting discovery. There is a skill in discerning between insignificant artifacts in the data and something new that is genuine discovery.
This work provides a framework for other groups to target RAS more effectively. “The RAS protein, which was thought to be non-drug, is actually able to be targeted by drugs,” O’Bryan said.
The researchers are very hopeful that this discovery can be used more fully in the future. As cancers adapt and mutate to become resistant to therapeutics, new drugs based on this concept could serve as additional tools in the arsenal to treat cancer, he said.
The next step in the journey will be to find small molecules in MUSC’s library of compounds that can be used to target the mutant RAS in the same way as the R15 unibody. Since the R15 unibody cannot easily enter cells, O’Bryan explained that a small molecule targeting nucleotide-free mutant RAS proteins will be a more effective therapy.
“We are at a very good stage to exploit this mechanism,” O’Bryan said. “MUSC and Hollings have a very good culture of collaboration, which has helped move this project forward. MUSC’s access to the massive library of small molecules helps provide great chemical diversity and intellectual property potential.
The researchers believe that this research reveals a new window of opportunity for the development of new anti-cancer agents needed to improve patient outcomes.
Funding for this project was provided by: NCI P30 CA138313, NCI R01CA212608, Department of Veterans Affairs MERIT Award 1I01BX002095