title: PTEN deficiency is associated with reduced sensitivity to mTOR inhibitor in human bladder cancer through the unhampered feedback loop driving PI3K/Akt activation.
abstract: BACKGROUND
  Preclinical studies have shown that PTEN loss enhances sensitivity to mammalian target of Rapamycin (mTOR) inhibitors because of facilitated PI3K (phosphatidylinositol-3 kinase)/Akt activation and consecutive stimulation of the mTOR pathway. In patients with advanced transitional cell carcinoma (TCC) treated with the mTOR inhibitor everolimus, PTEN loss was, however, associated with resistance to treatment.
  
  
  METHODS
  Transitional cell carcinoma specimens, human bladder cancer cells and derived mouse xenografts were used to evaluate how the PTEN status influences the activity of mTOR inhibitors.
  
  
  RESULTS
  Transitional cell carcinoma patients with a shorter progression-free survival under everolimus exhibited PTEN deficiency and increased Akt activation. Moreover, PTEN-deficient bladder cancer cells were less sensitive to rapamycin than cells expressing wild-type PTEN, and rapamycin strikingly induced Akt activation in the absence of functional PTEN. Inhibition of Akt activation by the PI3K inhibitor wortmannin interrupted this rapamycin-induced feedback loop, thereby enhancing the antiproliferative effects of the mTOR inhibitor both in vitro and in vivo.
  
  
  CONCLUSIONS
  Facilitation of Akt activation upon PTEN loss can have a more prominent role in driving the feedback loop in response to mTOR inhibition than in promoting the mTOR pathway. These data support the use of both PI3K and mTOR inhibitors to treat urothelial carcinoma, in particular in the absence of functional PTEN.
authors.affiliation: 1] Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium [2] Pole of Molecular Imaging, Radiotherapy and Oncology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussels, Belgium [3] Department of Medical Oncology, Centre du Cancer, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Seront
authors.forename: A
authors.initials: A
authors.lastname: Pinto
authors.forename: C
authors.initials: C
authors.lastname: Bouzin
authors.forename: L
authors.initials: L
authors.lastname: Bertrand
authors.forename: J-P
authors.initials: JP
authors.lastname: Machiels
authors.forename: O
authors.initials: O
authors.lastname: Feron
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D017322:Clinical Trials, Phase II as Topic; D018572:Disease-Free Survival; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D000068338:Everolimus; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000077191:Wortmannin; D023041:Xenograft Model Antitumor Assays
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D000068338:Everolimus; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000077191:Wortmannin; C546842:MTOR protein, human; C494929:PTEN protein, human