Targeting MEK for the Treatment of Non–Small-Cell Lung Cancer

Abstract

Inhibition of the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway has been the focus of drug development for many years. The pathway is dysregulated in a significant percentage of solid tumors, including approximately 20% to 35% of non–small-cell lung cancers (NSCLC).1 Nevertheless, successful targeting of this pathway has been difficult to achieve.2 Inhibitors of RAS, the most commonly mutated gene in this pathway, have not generated successful results in clinical trials. Therefore, inhibition at other points along the pathway has been evaluated. MEK1 and MEK2 are threonine/tyrosine protein kinases that are phosphorylated by activated RAF and in turn, phosphorylate ERK1 and ERK2, leading to proliferation and migration. Mutations in RAS or RAF lead to a sustained oncogenic signal and predict response to MEK inhibition in laboratory models.3,4 Three MEK inhibitors and an Akt inhibitor were presented in this session at the 12th Annual Targeted Therapies of the Treatment of Lung Cancer and will be reviewed here.