Molecular mechanisms of resistance to therapeutic MEK inhibition in BRAF [V600E] cancer

Abstract

Aberrant activation of the mitogen activated protein kinase (MAPK) pathway is common in solid tumours. This hierarchical pathway consists of a three-tiered kinase casade of BRAF, MAPK kinase (MEK1/2) and the extracellular signal-regulated kinase (ERK1/2). Extracellular ligands activate the pathway by binding to receptors on the cell surface that signal through the small GTRase RAS to recruit and activate BRAF, which initiates a kinase cascade through MEK1/2 and ERK1/2 to activate downstream transcription factors involved in a range of biochemical processes including differentiation, proliferation, growth and survival. Mutations in BRAF occur at an estimated rate of 50-80% melanoma and 45% in thyroid carcinoma. The most common BRAF mutation is a single base pair change, T1799A, that results in a valine to glutamic acid change at position 600 in the BRAF polypeptide (BRAF V600E). This causes a conformational change in the BRAF protein leading to constitutive activation and oncogene addiction to the MAPK pathway.