Figure 1.

Resistance to BRAF inhibitors can occur through stromal extracellular signals (blue) leading to ERK reactivation upstream of MEK (orange) or to enhanced survival signaling(green). Pathway re-activation occurs through either activating NRAS mutations (*), loss of the RAS suppressor NF1, BRAF amplification or alternative splicing leading to BRAF truncations, overexpression or mutation of the MEK activators CRAF, MLK or COT/TPL2/MAP3K8 as well as MEK mutations (*). Enhanced survival signaling is brought about by the PI3K pathway [mutations in PI3K or AKT (*)] or for instance by over-expressed MITF. Stromal derived signals can emanate from fibroblasts or macrophages; thereby macrophages can release factors that directly act on melanoma cells or factors that activate fibroblasts.