Figure 1. Resistance to BRAF^V600 mutation inhibition driven by MAPK reactivation in melanoma.

Alterations in genes (red symbols) thought to contribute to acquired resistance by turning the MAPK pathway back-on after prolonged selection with BRAF inhibitors. These alterations include transcriptional upregulation of multiple receptor tyrosine kinases, transcriptional/mutational upregulation of KRAS or NRAS, BRAF^V600 mutant amplification or alternative splicing, and MEK1/2 mutations that result in so-called RAF-regulated MEK mutants. These genomic or non-genomic alterations converge on and augment two protein/protein interactions (shown as double-headed green arrows): “back-to-back” BRAF/BRAF (BRAF/CRAF) or “face-to-face” BRAF/MEK (CRAF/MEK) interactions. Adaptive resistance occurs early during the course of treatment and can result from relief of negative feedback, resulting in rebound levels of signals, including RTK-mediated RAS/RAF activation. The RTK implicated in adaptive vemurafenib resistance in colon cancer is thought to be EGFR, although multiple receptor tyrosine kinases can be upregulated simultaneously and redundantly activate the MAPK and/or PI3K-AKT pathways.