Since this is substantiated by ERK1/2 reactivation during a targeted therapy-resistant state in melanoma [157], copper restriction can lead to compensatory effects as exemplified by the use of sulfur nanoparticles (Nano-S), another copper-chelating compound that inhibits the BRAF/MEK/ERK pathway by reducing the level of phosphorylated MEK, but compensatory CTR1 overexpression has been reported [158]. This evidence concerns the gene CALCR and melanoma.