However, the effectiveness of these therapies is frequently restricted by resistance, particularly in BRAF V600E mutant melanoma (Cintolo et al., 2016[18]; Corazzari et al., 2015[20]), where MEK inhibition can reactivate ERK signaling (Yin et al., 2024[142]).Additionally, the tumor microenvironment, through factors such as interleukin-6 (IL-6), can activate the JAK/STAT pathway (Lesina et al., 2014[65]; Lu et al., 2023[77]), that synergizes with ERK signaling, further diminishing the efficacy of targeted therapies (Ryan et al., 2024[113]). This evidence concerns the gene MAPK1 and melanoma.