Causes of B-RAF(V600E) colon cancer
B-RAF(V600E) colon cancer is caused by a phosphomimetic mutation in the B-RAF protein. This V600E mutation replaces V600 valine, a medium-sized hydrophobic side chain, with E600 glutamine, a larger, charged side chain. This disrupts the hydrophobic interactions that maintain the inactive state of the B-RAF protein, and stabalizes the active conformation of the protein, resulting in its constitutive activation. The B-RAF protein belongs to an important and conserved cell signalling pathway in our body called the mitogen-activated protein kinase (MAPK) pathway. In this pathway, extracellular signals such as hormones and epidermal growth factors phosphorylates the RAS protein. Activated RAS then phosphorylates and activates RAF, which subsequently signals through MEK to activate ERK and its downstream effectors, thereby regulating important biological activities including cell proliferation, differentiation, growth and survival.
The constitutive activation of the B-RAF protein therefore results in overactivation of the entire MAPK signalling pathway, resulting in excessive signalling for cell growth, which eventually leads to cancer development.
Possibility of involvement of parallel pathway (PI3K) in the resistance mechanism of BRAF(V600E) colon cancer cells
The parallel activation of the phosphatidylinositol 3-kinase (PI3K) pathway, more specifically the cMET-PI3K-Tpl2 axis, is a possible explanation for the negative responses in BRAF(V600E) colon cancer patients to the novel GDC-0879 drug. The PI3K pathway plays a central role in the signaling of cellular processes including metabolism, growth and survival, and exists as one of the most frequently implicated signaling cascades in human cancers. cMET and Tpl2/COT-1 have also been demonstrated to be key resistance mechanisms in lung cancer and melanoma, respectively. This strongly suggests the intriguing possibility that activation of the PI3K pathway may cross-activate ERK in the MAPK pathway, thus allowing the resistant cancer cells to circumvent pharmacologic B-RAF inhibition.