Figure 3.

Pharmacological mechanisms underlying selective BRAF inhibition. In cells dependent on BRAF(V600E) (BRAF*) signaling, binding of a SBI such as PLX4720/4032 leads to attenuation of downstream MEK1/2 and ERK1/2 signaling. In RAS*-dependent cells (tan background shading), MEK and ERK are paradoxically stimulated by RAF inhibitors. In one model (i), binding of SBIs to BRAF leads to binding between BRAF/CRAF and increased stimulation of CRAF by RAS*, since BRAF activity is inhibited by the SBI. In another model (ii), RAS* mediates dimerization between RAF partners; when one RAF molecule within the dimer is inhibited by a RAF inhibitor (RAFi), there is transactivation of the uninhibited partner, thereby stimulating downstream signaling. In cells with acquired SBI resistance, several mechanisms have been described. BRAF gene amplification, a BRAF(V600E) splice variant (p61BRAF*), MEK1 mutation (MEK1*), secondary NRAS activation (NRAS*), and stimulation of PDGF-R or IGF-R have all been observed in tumors samples. Overexpression of CRAF and COT1 has been shown to confer resistance in functional screens.