PHLDA1 and melanoma: Indeed, all the components of the 6-gene score are known transcriptional targets of the MEK–ERK pathway.21,31–36 Furthermore, four of six of these genes (DUSP4, DUSP6, PHLDA1 and SPRY2) are negative regulators of ERK pathway activity, forming part of a regulatory feedback loop.21,31,33,36,37 Consistent with the ability of mutant NRAS to activate MEK–ERK signalling, our results suggest that NRAS mutant melanoma is associated with a higher MEK 6 gene expression score than NRAS wild-type melanoma (Fig. 1b).