Figure 1. Targeting MEK in cancer. According to findings published in Nature, two classes of MEK inhibitors exhibit different effects in K-Ras (KRAS)- and BRAF-mutant backgrounds. In cancer cells, BRAF or Ras proteins often acquire activating mutations that allow them to become independent of growth factor (GF) and receptor tyrosine kinase (RTK) function and to overstimulate their downstream signaling elements. BRAF strongly phosphorylates and activates MEK as its primary downstream target. KRAS activates MEK less strongly than BRAF but also drives phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB; PKBA; AKT; AKT1)
signaling. MEK-ERK and PI3K-AKT signaling can cooperate to promote cancer cell proliferation.

In cancer cells that develop resistance to BRAF inhibitors like Zelboraf vemurafenib, BRAF trans-activates wild-type CRAF (RAF1), and the BRAF-CRAF complex is further stimulated by elevated Ras activity. Ras activity can be enhanced by de novo mutation of neuroblastoma Ras viral (v-Ras) oncogene (NRAS) or hyperactive RTKs.