Limiting gene interactions can prevent melanoma

By The Science Advisory Board staff writers

June 27, 2022 -- When it comes to melanoma, a new study published this month in the journal Nature Communications found that limiting interactions of the genes NRAS-BRAF could prevent the formation of the NRAS mutant that causes melanoma.

The research team, led by Christian Burd, an associate professor from the department of cancer biology and genetics at the Ohio State University in Columbus, OH, said NRAS-mutant cancers, like melanoma, are difficult to treat and each cancer type seems to prefer a specific "flavor" of mutant NRAS. He and his colleagues sought to determine why and developed genetically engineered models that would allow them to activate different NRAS-mutant variations in melanocytes.

They generated eight conditional, knock-in mouse models and showed that rare melanoma mutants (NRAS G12D, G13D, G13R, Q61H, and Q61P) are poor drivers of spontaneous melanoma formation. However, common melanoma mutants (NRAS Q61R, Q61K, or Q61L) induce rapid tumor onset with high penetrance. Molecular dynamics simulations, combined with cell-based protein-protein interaction studies, demonstrate that melanomagenic NRAS mutants form intramolecular contacts that enhance BRAF binding affinity, BRAF-CRAF heterodimer formation, and MAPK > ERK signaling. The results establish a mechanistic basis for the enrichment of specific NRAS mutants in human melanoma.

In other words, 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 like sun exposure, the researchers found.

The study was supported with funding from the Damon Runyon Foundation and the Pelotonia Graduate Fellowship of study coauthor Brandon Murphy, who is now a postdoctoral fellow at the University of Utah.

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