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 Nras^Q61R knock-in allele to similarly designed Kras^G12D and Nras^G12D alleles. With concomitant p16^INK4a inactivation, Kras^G12D or Nras^Q61R expression efficiently promoted melanoma in vivo, whereas Nras^G12D did not. In addition, Nras^Q61R mutation potently cooperated with Lkb1/Stk11 loss to induce highly metastatic disease. Functional comparisons of Nras^Q61R and Nras^G12D revealed little difference in the ability of these proteins to engage PI3K or RAF. Instead, Nras^Q61R showed enhanced nucleotide binding, decreased intrinsic GTPase activity, and increased stability when compared with Nras^G12D. This work identifies a faithful model of human NRAS-mutant melanoma, and suggests that the increased melanomagenecity of Nras^Q61R over Nras^G12D 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 NRAS^Q61R, but not NRAS^G12D, drives melanoma formation. Cancer Discov; 4(12); 1418–29. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 1355