Loss of NF1 in Cutaneous Melanoma Is Associated with RAS Activation and MEK Dependence
- 15 April 2014
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 74 (8), 2340-2350
- https://doi.org/10.1158/0008-5472.can-13-2625
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. Cancer Res; 74(8); 2340–50. ©2014 AACR.Other Versions
This publication has 47 references indexed in Scilit:
- Genomic and Biological Characterization of Exon 4 KRAS Mutations in Human CancerCancer Research, 2010
- 4E-BP1 Is a Key Effector of the Oncogenic Activation of the AKT and ERK Signaling Pathways that Integrates Their Function in TumorsCancer Cell, 2010
- Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiationNature Biotechnology, 2010
- Ensembl's 10th yearNucleic Acids Research, 2009
- Proteasomal and Genetic Inactivation of the NF1 Tumor Suppressor in GliomagenesisCancer Cell, 2009
- Mechanisms in the pathogenesis of malignant tumours in neurofibromatosis type 1The Lancet Oncology, 2009
- V600E BRAF is associated with disabled feedback inhibition of RAF–MEK signaling and elevated transcriptional output of the pathwayProceedings of the National Academy of Sciences of the United States of America, 2009
- Comprehensive genomic characterization defines human glioblastoma genes and core pathwaysNature, 2008
- Lineage dependency and lineage-survival oncogenes in human cancerNature Reviews Cancer, 2006
- The RIN: an RNA integrity number for assigning integrity values to RNA measurementsBMC Molecular Biology, 2006