Ras mutations were found in secondary skin lesions of melanoma patients treated with Raf inhibitors [109,110], and the significance of Ras activation for Raf inhibitor-induced tumor development was verified in mouse models in which Ras activation was induced either by chemical carcinogenesis [110] or by targeting the GEF SOS to the plasma membrane of basal keratinocytes [92]. This evidence concerns the gene RAF1 and melanoma.