Fig. 1

The BRAF pathway. a Activated BRAF-mutated protein leads to phosphorylation and activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)1/2 proteins, which subsequently phosphorylate and activate ERK1/2 proteins. After activation, ERK proteins phosphorylate a variety of substrates, including multiple transcription factors and regulate several key cellular activities, such as proliferation, differentiation and angiogenesis, to promote tumour growth. b Inhibition of BRAF suppresses the ERK-mediated negative feedback of the epidermal growth factor receptor (EGFR), resulting in EGFR activation, formation of RAF protein dimers and CRAF-mediated reactivation of the MAPK signalling pathway. c Preclinical studies have shown efficacy with combination drugs targeting BRAF (BRAF inhibitor), MEK (MEK inhibitor) and EGFR (anti-EGFR monoclonal antibody); this triplet combination might be an interesting therapeutic approach in patients with BRAF-mutated mCRC. d Crosstalk between the RAS/BRAF/MEK/ERK and the PI3K/AKT/mammalian target of rapamycin (mTor) signalling pathways after BRAF inhibition could play a determinant role in cell survival. Combining BRAF, EGFR and PI3K inhibitors could constitute another interesting therapeutic approach in patients with BRAF-mutated mCRC