Inhibitors of the ERK Mitogen-Activated Protein Kinase Cascade for Targeting RAS Mutant Cancers

Abstract Although recent success in identifying direct inhibitors of mutant Ras has begun to challenge the perception that Ras is “undruggable,” the successful transition of these hits to the clinic remains uncertain. Therefore, current efforts to develop anti-Ras inhibitors are focused on indirect approaches, with inhibitors of the downstream effectors of Ras signaling having attracted the greatest current interest. Of the multitude of effectors, the Raf–MEK–ERK mitogen-activated protein kinase (MAPK) cascade is arguably the most attractive target for these efforts. In this chapter, we review the evidence for a key driver role for the ERK MAPK cascade in RAS mutant cancers and the status of efforts to develop inhibitors of MEK1/2 and ERK1/2 to block this pathway.