Targeting the mTOR, PI3K, and AKT pathways in melanoma

A comprehensive analysis of critical oncogenic signaling pathways in melanoma is leading to new therapeutic approaches for the treatment of this disease. The present chapter addresses the pathways that communicate signals from membrane receptors and selected other intracellular processes that lead to the activation of the mammalian target of rapamycin (mTOR) and its downstream substrates. mTOR exists in two distinct, but related, molecular complexes that control a multitude of cellular processes and intercellular interactions, the normal function of which is to regulate cell metabolism, growth and proliferation, apoptosis, and interactions with the microenvironment. In malignancy, abnormal activation of these pathways either directly or indirectly through other oncogenic signals gives rise to increased proliferation and cell growth, resistance to cell death, and other metabolic and intercellular alterations that are characteristic of the transformed phenotype. Current understanding of mTOR activity, its control by other molecules, and its role in various aspects of malignancy, including preclinical and current clinical data regarding its therapeutic targeting by pharmacologic agents, will be detailed in this chapter.