PI3K/Akt/mTOR signaling

Interest into targeting the phosphoinositide 3-kinase, AKT, and mammalian target of rapamycin (PI3K/AKT/mTOR) signaling network in cancer has increased by the recent disclosure that PIK3CA of the PI3K pathway is the second most frequently mutated gene in cancer. Overall, a number of elements of the PI3K/AKT/mTOR pathway are frequently mutated in cancer, thus stimulating strong interest for PI3K-specific drug development. The PI3K/Akt/mTOR signaling pathways is crucial to many aspects of cell growth and survival, in physiological as well as in pathological conditions. Under normal conditions, PI3K activation is initiated through extracellular binding of ligands (e.g. EGF, HER2, KIT ligand, PDGF, MET), which in turn triggers the activation of corresponding receptor tyrosine kinases (RTK). The plethora of receptors may include insulin receptor (IR), Fms-like tyrosine kinase 3 (FLT3), c-KIT, epidermal growth factor receptor (EGFR), platelet derived growth factor receptor alpha (PDGFRa), fibroblast growth factor receptor (FGFR), colony-stimulating growth factor I (CSF-I) or insulin-like growth factor I (IGF-I).
Many genes belonging to the PI3K/Akt pathway have been implicated in the pathophysiology of solid tumors and sensitivity/resistance to chemotherapy. More and more studies are now focusing on the translational relevance of targeting these pathways in cancer therapy.Currently mTOR inhibitors are approved for several indications, and there are several novel PI3K/AKT/mTOR inhibitors in clinical trials, and some demonstrate promise for the treatment of hyperactivated PI3K tumors. A better understanding of the pathway oncogenic mechanisms, different ways in which the signaling network is upregulated, and properties of distinct PI3K/AKT/mTOR genetic alterations will guide future strategic approaches for rational combination therapies.