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The majority of human melanomas harbor activating mutations in either theBRAForNRASgene. To date, the role of oncogenicNRASin melanoma remains poorly defined and no current therapies are directed at specifically suppressing oncogenicNRASin human melanoma tumors. The aim of our study, therefore, was to investigate the effects of suppressing oncogenicNRASin human melanoma cell linesin vitro. Using both small interfering RNA- and plasmid based-RNA interference techniques, oncogenicNRASwas specifically suppressed in 2 human melanoma cell lines, 224 and BL, which harbor a codon 61 CAA (glutamine) to CGA (arginine)NRASmutation. Suppression of oncogenicNRASin these cell lines resulted in increased apoptosis. Furthermore, in 224 cells we demonstrated decreased phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, and reduced expression of NF-κB and cyclin D1 in the N-Ras signaling pathway. In contrast, RNA interference directed at wild-type (WT)NRAShad no significant effect on apoptosis of 224 cells or 2 human melanoma cell lines (A375 and 397) containing WTNRASbut a codon 600 GTG (valine) to GAG (glutamate) mutation inBRAF. These data suggest that oncogenicNRASis important for avoidance of apoptosis in melanomas that harbor the codon 61NRASmutation and emphasizes oncogenicNRASas a therapeutic target in patients with tumors that harbor this mutation. © 2005 Wiley-Liss, Inc.