The PKB/AKT Pathway in Cancer

PKB/AKT constitutes an important pathway that regulates the signaling of multiple essential biological processes. PTEN is a dual protein/lipid phosphatase whose main substrate is phosphatidyl-inositol,3,4,5 triphosphate (PIP3), the product of PI3K. Increases in PIP3 result in the recruitment of PDK1 and AKT to the membrane where they are activated. Furthermore, PI3K can be activated by direct binding to oncogenic Ras proteins. Many components of this pathway have been described as genetically altered in cancer. PTEN activity is lost by mutations, deletions or promoter methylation at high frequency in many primary and metastatic human cancers, and some germline mutations of PTEN are found in several familial cancer predisposition syndromes. Activating mutations of PI3K occur in human tumors and confer tumorigenic properties to cells in culture. Taken together, this evidence indicates that the AKT pathway is a promising potential target for cancer chemotherapy. Indeed, many companies and academic laboratories have initiated a variety of approaches to inhibit the pathway at different points. Essentially, PI3Ks, PDK1, AKT and mTOR are heavily targeted for therapy in different ways. These proteins are kinases, which are very “druggable” targets a priori, and, according to the “addiction hypothesis”, cancer cells with the activated pathway will be more dependent on its activity for their survival.