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The American Cancer Society estimates there will be 1.
9 million new cancer cases this year
.
Due to the urgent need for more effective treatments, researchers have been searching for elusive treatments that can affect many cancers
O'bryan, a professor in the Department of Cellular and Molecular Pharmacology and Experimental Therapeutics at the Medical University of South Carolina, said: "RAS is one of the most central and critical regulators of cell proliferation and the most mutated in cancer
.
Mutations RAS drives tumor growth
The RAS protein family is mutated in nearly 20% of human tumors; however, little progress has been made in drug development targeting this target
.
"Think of RAS as a smooth ball that doesn't allow anything to bind to it
The new drug, sotorasib, targets a mutated form of RAS that occurs in less than 3 percent of human cancers, so the new drug isn't very useful for many types of cancer, O'bryan said
.
His new approach to targeting mutant RAS therapy is more promising because it has the potential to work with multiple mutated forms of RAS in multiple cancers
Pancreatic, lung and colorectal cancers are three of the four deadliest cancers, and their growth is driven by mutations in the RAS protein
.
Therefore, successfully targeting the mutated RAS gene has huge implications for patients," O'bryan said
The challenge with targeting RAS is how it works
.
It has "on" and "off" states, which are regulated by binding to other molecules called nucleotides
O'bryan's collaborator Shohei Koide, Ph.
D.
, from the NYU Perlmutter Cancer Center, developed the monomer technology to overcome the challenges of targeting nucleotide-free RAS
.
Monomers are small synthetic binding proteins that can be engineered to attach to cellular targets in and out of cells
Targeting nucleotide-free RAS with an R15 monomer allowed researchers to better understand RAS biochemistry and uncover opportunities to disrupt its cancer-promoting activity
.
Using a mix of biochemical techniques, cell culture work and animal models, they found that the R15 monomer blocked multiple forms of RAS mutants
"We were surprised to find that many RAS mutants can unlock nucleotides that R15 monomers can block," O'Brien said
.
"This is a good sign that more than 50 percent of oncogenic RAS mutations may be responsible for Inhibitors that bind nucleotide-free RAS are sensitive
.
This makes targeting nucleotide-free RAS a viable approach to suppress many RAS-driven mutant tumors
.
"
O'Brien says there are often unexpected discoveries in a research career
.
"We were stuck with early data because it had no immediate meaning
.
However, this was an exciting finding
.
There's a trick to distinguishing unimportant artefacts from real discoveries in the data
.
"
This work provides a framework for other groups to target RAS in a more efficient manner
.
"The RAS protein was once thought to be untreatable, but in fact it can be treated with drugs
.
"
The researchers are hopeful that the discovery will find wider application in the future
.
While cancers do adapt and mutate to become resistant to treatments, new drugs based on this concept could become additional tools for treating cancer, he said
.
The next step in the research will be to find small molecules in MUSC's compound library that can target mutant RAS in the same way as the R15 monomer
.
Because the R15 monomer does not easily enter cells, O'bryan explained that a small molecule targeting the nucleotide-free mutant RAS protein would be a more effective treatment
.
"We're in a good stage of exploiting this mechanism," O'Bryan said
.
"MUSC and Hollins have a very good culture of collaboration, which helps to move this project forward.
MUSC's access to a large library of small molecules helps provide a lot of chemical diversity and intellectual property potential
.
"
The researchers believe this study provides new opportunities for developing new anticancer drugs to improve patient outcomes
.
Funding for this project was provided by: NCI P30 CA138313, NCI R01CA212608, U.
S.
Department of Veterans Affairs Merit Award 1I01BX002095
Journal Reference :
Imran Khan, Akiko Koide, Mariyam Zuberi, Gayatri Ketavarapu, Eric Denbaum, Kai Wen Teng, J.
Matthew Rhett, Russell Spencer-Smith, G.
Aaron Hobbs, Ernest Ramsay Camp, Shohei Koide, John P.
O'Bryan.
Identification of the nucleotide-free state as a therapeutic vulnerability for inhibition of selected oncogenic RAS mutants .
Cell Reports , 2022; 38(6): 110322 DOI: 10.
1016/j.
celrep.
2022.
110322
