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

Publication ,  Journal Article
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 ...
Published in: Cancer Discov
December 2014

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.

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Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

December 2014

Volume

4

Issue

12

Start / End Page

1418 / 1429

Location

United States

Related Subject Headings

  • Tumor Burden
  • Proto-Oncogene Proteins B-raf
  • Protein Serine-Threonine Kinases
  • Protein Binding
  • Phosphatidylinositol 3-Kinases
  • Oncogene Proteins, Fusion
  • Neoplasm Metastasis
  • Mutation
  • Mitogen-Activated Protein Kinases
  • Mice
 

Citation

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Burd, C. E., Liu, W., Huynh, M. V., Waqas, M. A., Gillahan, J. E., Clark, K. S., … Sharpless, N. E. (2014). Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma. Cancer Discov, 4(12), 1418–1429. https://doi.org/10.1158/2159-8290.CD-14-0729
Burd, Christin E., Wenjin Liu, Minh V. Huynh, Meriam A. Waqas, James E. Gillahan, Kelly S. Clark, Kailing Fu, et al. “Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma.Cancer Discov 4, no. 12 (December 2014): 1418–29. https://doi.org/10.1158/2159-8290.CD-14-0729.
Burd CE, Liu W, Huynh MV, Waqas MA, Gillahan JE, Clark KS, et al. Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma. Cancer Discov. 2014 Dec;4(12):1418–29.
Burd, Christin E., et al. “Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma.Cancer Discov, vol. 4, no. 12, Dec. 2014, pp. 1418–29. Pubmed, doi:10.1158/2159-8290.CD-14-0729.
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. Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma. Cancer Discov. 2014 Dec;4(12):1418–1429.

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

December 2014

Volume

4

Issue

12

Start / End Page

1418 / 1429

Location

United States

Related Subject Headings

  • Tumor Burden
  • Proto-Oncogene Proteins B-raf
  • Protein Serine-Threonine Kinases
  • Protein Binding
  • Phosphatidylinositol 3-Kinases
  • Oncogene Proteins, Fusion
  • Neoplasm Metastasis
  • Mutation
  • Mitogen-Activated Protein Kinases
  • Mice