title: Current clinical regulation of PI3K/PTEN/Akt/mTOR signalling in treatment of human cancer.
abstract: OBJECTIVE
  PTEN is an essential tumour suppressor gene which encodes a phosphatase protein that antagonises the PI3K/Akt/mTOR antiapoptotic pathway. Impairment of this tumour suppressor pathway potentially becomes a causal factor for development of malignancies. This review aims to assess current understanding of mechanisms of dysfunction involving the PI3K/PTEN/Akt/mTOR pathway linked to tumorigenesis and evaluate the evidence for targeted therapy directed at this signalling axis.
  
  
  METHODS
  Relevant articles in scientific databases were identified using a combination of search terms, including "malignancies", "targeted therapy", "PTEN", and "combination therapy". These databases included Medline, Embase, Cochrane Review, Pubmed, and Scopus.
  
  
  RESULTS
  PI3K/PTEN expression is frequently deregulated in a majority of malignancies through genetic, epigenetic, and post-transcriptional modifications. This contributes to the upregulation of the PI3K/Akt/mTOR pathway which has been the focus of intense clinical studies. Targeted agents aimed at this pathway offer a novel treatment approach in a variety of haematologic malignancies and solid tumours. Compared to single-agent use, greater response rates were obtained in combination regimens, supporting further investigation of suitable drug combinations in a broad spectrum of malignancies.
  
  
  CONCLUSIONS
  Activation of the PI3K/PTEN/Akt/mTOR pathway is implicated both in the pathogenesis of malignancies and development of resistance to anticancer therapies. Therefore, PI3K/Akt/mTOR inhibitors are a promising therapeutic option, in association with systemic cytotoxic and biological therapies, to enable sustained clinical outcomes in cancer treatment. Therapeutic strategies could be tailored according to appropriate biomarkers and patient-specific mutation profiles to maximise benefit of combination therapies.
authors.affiliation: Adult Cancer Program, Sarcoma and Nano-oncology Group, Faculty of Medicine, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Room 209, Randwick, Sydney, NSW, 2052, Australia.
authors.forename: Hui Jun
authors.initials: HJ
authors.lastname: Lim
authors.forename: Philip
authors.initials: P
authors.lastname: Crowe
authors.forename: Jia-Lin
authors.initials: JL
authors.lastname: Yang
mesh_terms: D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C494929:PTEN protein, human