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PTEN deficiency is associated with reduced sensitivity to mTOR inhibitor in human bladder cancer through the

E Seront1, A Pinto, C Bouzin

  • 11] 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.

British Journal of Cancer
|August 31, 2013
PubMed
Abstract

Insights

PTEN loss in urothelial carcinoma patients treated with mTOR inhibitors like everolimus leads to resistance. Combining PI3K and mTOR inhibitors may overcome this resistance by blocking feedback Akt activation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Preclinical data suggested PTEN loss sensitizes cells to mTOR inhibitors.
  • However, clinical data in advanced urothelial carcinoma (TCC) showed PTEN loss correlated with everolimus resistance.

Purpose of the Study:

  • To investigate the role of PTEN status in mediating response to mTOR inhibitors in TCC.
  • To elucidate the mechanisms behind PTEN loss-associated resistance.

Main Methods:

  • Analysis of TCC specimens, human bladder cancer cells, and mouse xenografts.
  • Evaluation of PTEN status, Akt activation, and response to mTOR inhibitors (rapamycin, everolimus).
  • Assessment of combined PI3K and mTOR inhibition.

Main Results:

  • PTEN-deficient TCC patients had shorter progression-free survival and increased Akt activation with everolimus.
  • PTEN-deficient cells showed reduced sensitivity to rapamycin, with rapamycin inducing Akt activation.
  • Inhibition of Akt activation by a PI3K inhibitor (wortmannin) reversed this feedback loop, enhancing anti-proliferative effects.

Conclusions:

  • PTEN loss promotes a feedback loop via Akt activation in response to mTOR inhibition, driving resistance.
  • Combined PI3K and mTOR inhibition is a promising strategy for urothelial carcinoma, especially in PTEN-deficient cases.

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