PTEN deficiency is associated with reduced sensitivity to mTOR inhibitor in human bladder cancer through the unhampered feedback loop driving PI3K/Akt activation

Br J Cancer. 2013 Sep 17;109(6):1586-92. doi: 10.1038/bjc.2013.505. Epub 2013 Aug 29.

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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Transitional Cell / drug therapy*
  • Carcinoma, Transitional Cell / enzymology
  • Carcinoma, Transitional Cell / pathology
  • Cell Line, Tumor
  • Clinical Trials, Phase II as Topic
  • Disease-Free Survival
  • Drug Interactions
  • Enzyme Activation / drug effects
  • Everolimus
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • PTEN Phosphohydrolase / deficiency*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Sirolimus / administration & dosage
  • Sirolimus / analogs & derivatives
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / enzymology
  • Urinary Bladder Neoplasms / pathology
  • Wortmannin
  • Xenograft Model Antitumor Assays

Substances

  • Androstadienes
  • Antineoplastic Agents
  • Everolimus
  • Phosphatidylinositol 3-Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Sirolimus
  • Wortmannin