Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of RAS mutant cancers

Abstract

The three RAS genes comprise the most frequently mutated oncogene family in human cancer; furthermore, substantial experimental evidence supports their key driver roles in cancer development and growth. Consequently, there has been considerable interest and effort in developing therapeutic approaches for blocking aberrant Ras function for cancer treatment. Despite over three decades of intensive effort, to date no effective anti-Ras therapeutic approaches have reached the clinic. Currently, the most promising direction involves inhibitors of Ras effector signaling, with the Raf-MEK-ERK mitogen-activated protein kinase cascade the most intensively pursued. Presently, there are at least 33 inhibitors of this pathway under clinical evaluation. In this chapter, we provide a summary of this key Ras effector signaling network and the efforts to target the Raf-MEK-ERK cascade for the treatment of RAS mutant cancers.