Enhanced BRAF engagement by NRAS mutants capable of promoting melanoma initiation

Brandon M. Murphy, Elizabeth M. Terrell, Venkat R. Chirasani, Tirzah J. Weiss, Rachel E. Lew, Andrea M. Holderbaum, Aastha Dhakal, Valentina Posada, Marie Fort, Michael S. Bodnar, Leiah M. Carey, Min Chen, Craig J. Burd, Vincenzo Coppola, Deborah K. Morrison, Sharon L. Campbell and Christin E. Burd ()
Additional contact information
Brandon M. Murphy: The Ohio State University
Elizabeth M. Terrell: Laboratory of Cell and Developmental Signaling, National Cancer Institute-Frederick
Venkat R. Chirasani: University of North Carolina at Chapel Hill
Tirzah J. Weiss: The Ohio State University
Rachel E. Lew: The Ohio State University
Andrea M. Holderbaum: The Ohio State University
Aastha Dhakal: The Ohio State University
Valentina Posada: The Ohio State University
Marie Fort: The Ohio State University
Michael S. Bodnar: The Ohio State University
Leiah M. Carey: University of North Carolina at Chapel Hill
Min Chen: The Ohio State University
Craig J. Burd: The Ohio State University
Vincenzo Coppola: The Ohio State University
Deborah K. Morrison: Laboratory of Cell and Developmental Signaling, National Cancer Institute-Frederick
Sharon L. Campbell: University of North Carolina at Chapel Hill
Christin E. Burd: The Ohio State University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract A distinct profile of NRAS mutants is observed in each tumor type. It is unclear whether these profiles are determined by mutagenic events or functional differences between NRAS oncoproteins. Here, we establish functional hallmarks of NRAS mutants enriched in human melanoma. We generate eight conditional, knock-in mouse models and show that rare melanoma mutants (NRAS G12D, G13D, G13R, Q61H, and Q61P) are poor drivers of spontaneous melanoma formation, whereas 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, reveal that melanomagenic NRAS mutants form intramolecular contacts that enhance BRAF binding affinity, BRAF-CRAF heterodimer formation, and MAPK > ERK signaling. Along with the allelic series of conditional mouse models we describe, these results establish a mechanistic basis for the enrichment of specific NRAS mutants in human melanoma.

Date: 2022
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DOI: 10.1038/s41467-022-30881-9

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