Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence

Moriah H. Nissan, Christine A. Pratilas, Alexis M. Jones, Ricardo Ramirez, Helen Won, Cailian Liu, Shakuntala Tiwari, Li Kong, Aphrothiti J. Hanrahan, Zhan Yao, Taha Merghoub, Antoni Ribas, Paul B. Chapman, Rona Yaeger, Barry S. Taylor, Nikolaus Schultz, Michael F. Berger, Neal Rosen, David B. Solit

Research output: Contribution to journalArticle

Abstract

Melanoma is a disease characterized by lesions that activate ERK. Although 70% of cutaneous melanomas harbor activating mutations in the BRAF and NRAS genes, the alterations that drive tumor progression in the remaining 30% are largely undefined. Vemurafenib, a selective inhibitor of RAF kinases, has clinical utility restricted to BRAF-mutant tumors. MEK inhibitors, which have shown clinical activity in NRAS-mutant melanoma, may be effective in other ERK pathway-dependent settings. Here, we investigated a panel of melanoma cell lines wild type for BRAF and NRAS to determine the genetic alteration driving their transformation and their dependence on ERK signaling in order to elucidate a candidate set for MEK inhibitor treatment. A cohort of the BRAF/RAS wild type cell lines with high levels of RAS-GTP had loss of NF1, a RAS GTPase activating protein. In these cell lines, the MEK inhibitor PD0325901 inhibited ERK phosphorylation, but also relieved feedback inhibition of RAS, resulting in induction of pMEK and a rapid rebound in ERK signaling. In contrast, the MEK inhibitor trametinib impaired the adaptive response of cells to ERK inhibition, leading to sustained suppression of ERK signaling and significant antitumor effects. Notably, alterations in NF1 frequently co-occurred with RAS and BRAF alterations in melanoma. In the setting of BRAF(V600E), NF1 loss abrogated negative feedback on RAS activation, resulting in elevated activation of RAS-GTP and resistance to RAF, but not MEK, inhibitors. We conclude that loss of NF1 is common in cutaneous melanoma and is associated with RAS activation, MEK-dependence, and resistance to RAF inhibition.

Original languageEnglish (US)
Pages (from-to)2340-2350
Number of pages11
JournalCancer Research
Volume74
Issue number8
DOIs
StatePublished - Apr 15 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Nissan, M. H., Pratilas, C. A., Jones, A. M., Ramirez, R., Won, H., Liu, C., Tiwari, S., Kong, L., Hanrahan, A. J., Yao, Z., Merghoub, T., Ribas, A., Chapman, P. B., Yaeger, R., Taylor, B. S., Schultz, N., Berger, M. F., Rosen, N., & Solit, D. B. (2014). Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence. Cancer Research, 74(8), 2340-2350. https://doi.org/10.1158/0008-5472.CAN-13-2625