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

Authors: 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.
Article Title: Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence
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. © 2014 American Association for Cancer Research.
Keywords: signal transduction; mitogen activated protein kinase; controlled study; protein expression; protein phosphorylation; human cell; cancer resistance; cell transformation; melanoma cell; neurofibromin; negative feedback; b raf kinase; braf gene; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; oncogene n ras; selumetinib; vemurafenib; trametinib; human; priority journal; article; binimetinib
Journal Title: Cancer Research
Volume: 74
Issue: 8
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2014-04-15
Start Page: 2340
End Page: 2350
Language: English
DOI: 10.1158/0008-5472.can-13-2625
PROVIDER: scopus
PMCID: PMC4005042
PUBMED: 24576830
Notes: Cancer Res. -- Export Date: 2 June 2014 -- CODEN: CNREA -- Source: Scopus
Citation Impact
MSK Authors
  1. Neal Rosen
    398 Rosen
  2. Taha Merghoub
    291 Merghoub
  3. David Solit
    628 Solit
  4. Paul Chapman
    306 Chapman
  5. Rona Denit Yaeger
    164 Yaeger
  6. Shakuntala Tiwari
    8 Tiwari
  7. Cailian Liu
    51 Liu
  8. Li Kong
    1 Kong
  9. Michael Forman Berger
    569 Berger
  10. Nikolaus D Schultz
    317 Schultz
  11. Helen Hyeong-Eun Won
    101 Won
  12. Moriah Gabrielle Heller Nissan
    11 Nissan
  13. Zhan Yao
    37 Yao
  14. Ricardo   Ramirez
    19 Ramirez
  15. Alexis Maria Jones
    4 Jones