New agents and approaches for targeting the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR cell survival pathways

The Ras/Raf/MEK/ERK and PI3K/Akt/mTOR cascades are often activated by genetic alterations, either by mutations in upstream signaling molecules or by mutations in intrinsic pathway components. 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. These pathways have profound effects on proliferative, apoptotic, and differentiation pathways. Dysregulation of components of these pathways can contribute to: Malignant transformation, resistance to other pathway inhibitors, and chemotherapeutic drug resistance. This chapter will first briefly describe these pathways and then evaluate potential uses of Raf, MEK, PI3K, Akt, and mTOR inhibitors that have been investigated in preclinical and clinical investigations.