Targeting the Cellular Signaling: BRAF Inhibition and Beyond for the Treatment of Metastatic Malignant Melanoma

Figure 2

Representation of the resistance mechanisms to the vemurafenib. (a) Vemurafenib causes cell death by inhibiting V600E BRAF kinase activity and signaling transduction through the MAPK pathway. (b) New mutations in the NRAS causes heterodimerization of BRAF/CRAF and reactivation of the signaling pathway. (c) and (d) Phosphorylation of ERK independent of RAF stimulation is the result of the overexpression of COT (c) and of the additional mutation in MEK kinase (d). (e) Overexpression of PDGFRβ can lead to resistance to vemurafenib treatment independent from the continuous inhibition of the MAPK pathway.