Resistance mechanisms to genetic suppression of mutant NRAS in melanoma

James P. Robinson, Vito W. Rebecca, David A. Kircher, Mark R. Silvis, Inna Smalley, Geoffrey T. Gibney, Kristin J. Lastwika, Guo Chen, Michael A. Davies, Douglas Grossman, Keiran S.M. Smalley, Sheri L. Holmen, Matthew W. VanBrocklin

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Targeted therapies have revolutionized cancer care, but the development of resistance remains a challenge in the clinic. To identify rational targets for combination strategies, we used an established melanoma mouse model and selected for resistant tumors following genetic suppression of NRAS expression. Complete tumor regression was observed in all mice, but 40% of tumors recurred. Analysis of resistant tumors showed that the most common mechanism of resistance was overexpression and activation of receptor tyrosine kinases (RTKs). Interestingly, the most commonly overexpressed RTK was Met and inhibition of Met overcame NRAS resistance in this context. Analysis of NRAS mutant human melanoma cells showed enhanced efficacy of cytotoxicity with combined RTK and mitogen-activated protein kinase kinase inhibition. In this study, we establish the importance of adaptive RTK signaling in the escape of NRAS mutant melanoma from inhibition of RAS and provide the rationale for combined blockade of RAS and RTK signaling in this context.

Original languageEnglish (US)
Pages (from-to)545-557
Number of pages13
JournalMelanoma research
Issue number6
StatePublished - 2017

Bibliographical note

Funding Information:
The authors thank the members of the VanBrocklin, Smalley, Holmen, and Davies labs as well as S. Hughes, W. Pavan, R. DePinho, and L. Chin for providing mouse strains, reagents, and advice. They also thank the Huntsman Cancer Institute Vivarium staff for assistance. The authors acknowledge the use of the DNA sequencing core facility supported by P30CA042014 awarded to Huntsman Cancer Institute from the National Cancer Institute.

Funding Information:
This work was supported by Award Number R01CA158316 (to M.V.B.) and R01CA121118 from the National Cancer Institute (to S.L.H.) as well as P50CA168536 and R01CA161107 from the National Cancer Institute (to K.S.M.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.


  • Melanoma
  • Mouse model
  • NRAS
  • Resistance

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