These agents target BRAF (one of the three RAF kinase family members) and MEK, which are important kinases in the RAS-RAF-MEK-ERK (extracellular signal-regulated kinase) signaling pathway, which plays important roles in promoting cell proliferation, differentiation, and resistance to apoptosis.156 Activating BRAF mutations have been observed in up to 60% of melanomas, as well as in smaller proportions of other malignancies.157 Multitargeted TKI, such as sorafenib and regorafenib, target BRAF and its mutant forms as well as VEGFR tyrosine kinases. This evidence concerns the gene BRAF and melanoma.