A new study reveals important molecular information that could help scientists develop more effective treatment and prevention strategies for a hard-to-treat form of melanoma.
In this new report, researchers at Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) identify and describe key features of a genetic mutation responsible for 15 to 20% of all melanomas.
Using a preclinical laboratory model, the team establishes that the frequency with which a NRAS genetic mutation occurring in human melanoma is directly related to the ability of this genetic mutation to initiate the spontaneous formation of melanoma.
“This means that the properties of the mutant itself – rather than the ease with which this specific genetic mutation occurs – are the cause of cancer formation,” said corresponding author Christin Burd, associate professor of molecular genetics at the Ohio State University College of Arts and Sciences, Department of Molecular Genetics and a member of the OSUCCC – James Molecular Carcinogenesis and Chemoprevention Program.
NRAS mutant cancers are difficult to treat because effective therapies beyond immunotherapy do not yet exist. Each type of cancer seems to prefer a specific “flavor” of mutant NRAS, and it’s unclear why this is.”
Christin Burd, Study Corresponding Author and Associate Professor of Molecular Genetics, College of Arts and Sciences, Ohio State University
The OSUCCC – James wanted to know what was promoting melanoma NRAS mutants different from those that promote other types of cancer. Scientists say this knowledge could help researchers identify the early events necessary for melanoma to form and develop treatments that prevent the disease.
Burd and colleagues report their findings in the June 7, 2022 issue of Nature Communication.
Study design and methods
To conduct this study, OSUCCC-James researchers developed genetically modified models that would allow them to activate one of nine different NRAS-Mutant variations in melanocytes, the pigment cells that form melanoma.
“Amazingly, when we activated these genetic mutations, only those found in human disease caused the development of melanoma,” Burd said. “Some mutants have never led to melanoma, but we know that they cause leukaemia. This discovery shows that the selection of NRAS mutations is specific to each tumor type and occurs during cancer initiation, rather than in response to a specific mutagenic event such as sun exposure.”
Working with Sharon Campbell, a structural biologist at the University of North Carolina (UNC) Chapel Hill, and Debbie Morrison at the National Institutes of Health, Burd’s team identified slight variations in the outward-facing structure of NRAS melanoma-initiating mutants that made these proteins better able to interact with signaling pathways that stimulate melanoma growth.
“Now we will work to target this unique structural feature of melanoma-inducing NRAS mutants to prevent and/or treat disease,” Burd said. “Our work also demonstrates and confirms what was – until now – only speculation: that minor differences between RAS mutants determine what “flavors “can cause a particular cancer. Such a concept could be used to find vulnerabilities in other tumor types driven by RAS.
To facilitate similar findings, the team has generated eight new, publicly available genetically modified mouse models that will serve as an essential toolkit for the entire RAS community. Burd says these models can be used to activate and study the role of NRAS in other relevant cancer types such as colon cancer, leukemia, myeloma and thyroid cancer. They can also be used to study new drugs for these diseases.
Murphy, BM, et al. (2022) BRAF engagement enhanced by NRAS mutants able to promote melanoma initiation. Nature Communication. doi.org/10.1038/s41467-022-30881-9
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