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.