title: Targeting PI3 kinase/AKT/mTOR signaling in cancer.
abstract: The phosphatidylinositol 3 kinase (PI3K) pathway is one of the major pathways modulating cell growth, proliferation, metabolism, survival, and angiogenesis. Hyperactivation of this pathway is one of the most frequent occurrences in human cancer and is thus an obvious target for treatment of this disease. Currently there are 26 novel compounds targeting the PI3K pathway being assessed in more than 150 cancer-related clinical trials. Although this pathway is involved in many vital biologic functions, data emanating from these clinical trials indicate that these drugs are well tolerated. This review outlines the interaction of the PI3K pathway with other signaling cascades, highlights mechanisms involved in hyperactivation, discusses current therapeutics in cancer-related clinical trials that target this pathway, and, based on preclinical data, discusses possible leads on patient selection and combinational therapy, including targeting multiple components of the associated signaling network.
authors.affiliation: Division of Cancer Research, Peter MacCallum Cancer Centre, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.
authors.forename: Karen
authors.initials: K
authors.lastname: Sheppard
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Kinross
authors.forename: Benjamin
authors.initials: B
authors.lastname: Solomon
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pearson
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Phillips
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human