Contemporary treatment approaches for metastatic colorectal cancer driven by BRAF V600 mutations

Figure 1 Activation of the mitogen-activated protein kinase (RAS-RAF-mitogen-activated protein kinase kinase-extracellular signal-regulated kinase) pathway due to BRAF V600 mutations and current targeted therapy options for metastatic colorectal cancer patients bearing these mutations. A: In healthy cells, a growth factor binds to and activates receptor tyrosine kinases on the cell membrane, inducing their dimerization. Then, the Grb2/Sos complex is recruited to the membrane to initiate RAS activation. Activated RAS triggers dimerization (i.e., BRAF-BRAF or BRAF-CRAF) and activation of RAF proteins. RAF proteins activate the mitogen-activated protein kinase kinase-extracellular signal-regulated kinase (MEK-ERK) pathway to promote cell proliferation and survival; and B: In colorectal cancer cells bearing a BRAF V600 mutation, mutant BRAF proteins can signal as a monomer and potently activate the MEK-ERK pathway in a RAS independent manner, which accelerates tumor formation and progression. Drugs targeting BRAF (BRAF inhibitor) and MEK (MEK inhibitor) are currently used in the treatment of BRAF-mutant metastatic colorectal cancer (mCRC). The use of BRAF inhibitors suppresses the negative feedback from ERK to the epidermal growth factor receptor, resulting in the mitogen-activated protein kinase reactivation and the treatment resistance. Triplet inhibition of epidermal growth factor receptor, BRAF, and MEK is an emerging therapeutic approach for patients with BRAF-mutant mCRC. Crosstalk between the mitogen-activated protein kinase pathway and the PI3K and Wnt pathways can play a role in the survival of BRAF-mutant CRC cells and their resistance to BRAF inhibition. The PI3K and Wnt inhibitors may be part of the future treatment of BRAF-mutant mCRC.