Raf/MEK/ERK Signaling

The Ras/Raf/MEK/ERK cascade is often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Certain components of these pathways, RAS, NF1, BRAF, and MEK1 are also deregulated by mutations. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. This pathway has profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of components of this pathway can contribute to: resistance to other pathway inhibitors and chemotherapeutic drugs. Intense scientific, commercial, and clinical interest has developed over the past decade in elucidating the functions of this pathway in leukemia and other blood cancers. Targeting this pathways is often complex and can result in pathway activation depending on the presence of upstream mutations (e.g., Raf inhibitors induce Raf activation in cells with wild type RAF in the presence of mutant, activated RAS). Furthermore, targeting with inhibitors directed at two constituents of the same pathway may be a more effective approach. This chapter will first describe these pathways and then evaluate potential uses of Raf and MEK inhibitors that have been investigated in pre-clinical and clinical investigation