New molecular information could help develop more effective treatments for melanoma

A new study reveals important molecular information that could help scientists develop more effective treatment and prevention strategies for a difficult-to-treat form of melanoma skin cancer.

In this new report, researchers from 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 gene mutation responsible for 15 to 20% of all melanoma

Using a preclinical laboratory model, the team determines that the frequency with which a specific NRAS gene mutation occurring in human melanoma is directly related to the ability of that gene mutation to initiate spontaneous melanoma formation.

“This means that traits of the mutant itself — rather than the ease with which that particular gene mutation occurs — is what drives cancer formation,” said corresponding author Christin Burd, who is an associate professor of molecular genetics at the Ohio State University College of Arts and Sciences. Sciences, Department of Molecular Genetics and member of the OSUCCC – James Molecular Carcinogenesis and Chemoprevention Program.

NRAS mutated cancers are challenging to treat because effective therapies beyond immunotherapy do not yet exist. Each cancer type seems to prefer a specific ‘flavor’ of mutated NRAS, and it’s not clear why this is

Christin Burd, corresponding author of the study and associate professor of molecular genetics, College of Arts and Sciences, The Ohio State University

The OSUCCC – James wanted to know what made it melanoma-promoting NRAS mutants different from those that promote other cancer types. Scientists say this knowledge could help researchers pinpoint 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

Research design and methods

To conduct this study, OSUCCC-James researchers developed genetically engineered models that allow them to use one of nine different NRAS-mutant variations in melanocytes, the pigment cells that make up melanoma.

“Amazingly, when we activated these gene mutations, only those found in human disease caused melanoma to develop,” Burd said. “Some mutants have never led to melanoma, but we know that they cause leukemia. This finding shows that selection of NRAS mutations are specific to each tumor type and occur during cancer onset, 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 of the National Institutes of Health, Burd’s team identified that minor abnormalities in the outward-facing structure of NRAS mutants that can initiate melanoma, making these proteins better able to interact with the signaling pathways that stimulate melanoma growth.

“Now we will focus on this unique structural feature of the melanoma-inducing Nbreed mutants to prevent and/or treat the disease,” said Burd. “Our work also demonstrates and confirms what has hitherto been mere speculation: that small differences between the RAS mutants determine which ‘flavors’ can cause a particular cancer. Such a concept could be used to find vulnerabilities in other RAS-driven tumor types.”

To enable similar discoveries, the team has generated eight new and publicly available genetically engineered mouse models that will serve as an essential toolkit for the entire RAS community. Burd says these models could be used to activate and study the role of NRAS in other relevant cancers, such as colon cancer, leukemia, myeloma and thyroid cancer. They can also be used to research new drugs for these diseases.


Reference magazine:

Murphy, B. M., et al† (2022) Enhanced BRAF involvement by NRAS mutants that may promote melanoma initiation. nature

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