Handicapping the Race to Develop Inhibitors of the Phosphoinositide 3-Kinase/Akt/Mammalian Target of Rapamycin Pathway

• Published in: Clinical cancer research 2006-02, Vol.12 (3), p.679-689
• Main Authors: Granville, Courtney A, Memmott, Regan M, Gills, Joell J, Dennis, Phillip A
• Format: Article
• Language: English
• Subjects: 3-Phosphoinositide-Dependent Protein Kinases; Animals; cancer therapy; Gene Targeting - methods; Humans; kinase; Molecular Structure; molecular targets; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Kinases - drug effects; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - antagonists & inhibitors; PTEN Phosphohydrolase - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Structure-Activity Relationship; TOR Serine-Threonine Kinases
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-1654

The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway controls many cellular processes that are important for the formation and progression of cancer, including apoptosis, transcription, translation, metabolism, angiogenesis, and cell cycle progression. Genetic alterations and biochemical activation of the pathway are frequent events in preneoplastic lesions and advanced cancers and often portend a poor prognosis. Thus, inhibition of the PI3K/Akt/mTOR pathway is an attractive concept for cancer prevention and/or therapy. Inhibitors of individual components, such as PI3K, PDK-1, Akt, and mTOR, are being developed at a rapid pace and have promise for improving the care of cancer patients. Here, we review the published data on inhibitors of the pathway and discuss relevant issues, such as the complex regulation of the pathway, the design of clinical trials, and the likelihood of finding a therapeutic index when targeting such a critical signaling pathway.