Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma.

Published

Journal Article

UNLABELLED: NRAS mutation at codons 12, 13, or 61 is associated with transformation; yet, in melanoma, such alterations are nearly exclusive to codon 61. Here, we compared the melanoma susceptibility of an NrasQ61R knock-in allele to similarly designed KrasG12D and NrasG12D alleles. With concomitant p16INK4a inactivation, KrasG12D or NrasQ61R expression efficiently promoted melanoma in vivo, whereas NrasG12D did not. In addition, NrasQ61R mutation potently cooperated with Lkb1/Stk11 loss to induce highly metastatic disease. Functional comparisons of NrasQ61R and NrasG12D revealed little difference in the ability of these proteins to engage PI3K or RAF. Instead, NrasQ61R showed enhanced nucleotide binding, decreased intrinsic GTPase activity, and increased stability when compared with NrasG12D. This work identifies a faithful model of human NRAS-mutant melanoma, and suggests that the increased melanomagenecity of NrasQ61R over NrasG12D is due to heightened abundance of the active, GTP-bound form rather than differences in the engagement of downstream effector pathways. SIGNIFICANCE: This work explains the curious predominance in human melanoma of mutations of codon 61 of NRAS over other oncogenic NRAS mutations. Using conditional "knock-in" mouse models, we show that physiologic expression of NRASQ61R, but not NRASG12D, drives melanoma formation.

Full Text

Duke Authors

Cited Authors

  • Burd, CE; Liu, W; Huynh, MV; Waqas, MA; Gillahan, JE; Clark, KS; Fu, K; Martin, BL; Jeck, WR; Souroullas, GP; Darr, DB; Zedek, DC; Miley, MJ; Baguley, BC; Campbell, SL; Sharpless, NE

Published Date

  • December 2014

Published In

Volume / Issue

  • 4 / 12

Start / End Page

  • 1418 - 1429

PubMed ID

  • 25252692

Pubmed Central ID

  • 25252692

Electronic International Standard Serial Number (EISSN)

  • 2159-8290

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-14-0729

Language

  • eng

Conference Location

  • United States