RAF1 and neoplasm: Several mechanisms of intrinsic or acquired resistance to RAF/MEK inhibitors were then elucidated: in most cases extracellular signal-regulated kinases (ERK) signaling results reactivated due to alterations that promote RAF stimulation (e.g., NRAS mutations, CRAF overexpression and RTK activation); whereas other mechanisms of resistance bypass the dependence of the tumor on RAF through, for example, MEK mutations or the overexpression of the mitogen-activated protein kinase (MAPK) agonist COT (9,10).