Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises.
The strategy of 'drugging the cancer kinome' has led to the successful development and regulatory approval of several novel molecular targeted agents. The spotlight is now shifting to the phosphatidylinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway as a key potential target. This review details the role of the pathway in oncogenesis and the rationale for inhibiting its vital components. The focus will be on the progress made in the development of novel therapies for cancer treatment, with emphasis placed on agents that have entered clinical development. Strategies involving horizontal and vertical blockade of the pathway, as well as the use of biomarkers to select appropriate patients and to provide proof of target modulation will also be highlighted. Finally, we discuss the issues and limitations involved with targeting the PI3K-AKT-mTOR pathway, and predict what the future may hold for these novel anticancer therapeutics.
Yap
Timothy A
TA
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, UK.
Garrett
Michelle D
MD
Walton
Mike I
MI
Raynaud
Florence
F
de Bono
Johann S
JS
Workman
Paul
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D015415:Biomarkers; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human