Antitumor effect of everolimus in preclinical models of high-grade gastroenteropancreatic neuroendocrine carcinomas

Neuroendocrinology. 2013;97(4):331-40. doi: 10.1159/000347063. Epub 2013 May 22.


Background/aims: While the range of therapeutic options for well-differentiated gastroenteropancreatic neuroendocrine tumors has recently increased with the emergence of targeted therapies, such as mTOR inhibitors, there is no recent progress in the treatment of poorly differentiated neuroendocrine carcinomas (PDNECs). Since PDNECs have been shown to strongly express mTOR pathway components, the aim of the present study was to assess the antitumor effect of the mTOR inhibitor everolimus in preclinical models of PDNECs.

Methods: The expression of mTOR pathway components and their response to everolimus were assessed in two neuroendocrine cell lines: STC-1 and GluTag. A xenograft model of intrahepatic dissemination in the nude mouse, based on the intrasplenic injection of either STC-1 and GluTag tumor cells, was used. Animals were started on everolimus treatment 3 days after injection. The effects of treatment on tumor growth, proliferative capacities, apoptosis and in situ expression of mTOR pathway components were assessed.

Results: The expression of mTOR pathway components was comparable in STC-1 and GluTag cells and in human PDNECs and could be inhibited in vitro by everolimus. In vivo, the tumor volume of STC-1 and GluTag xenografts was significantly reduced in treated animals (6.05 ± 1.84% as compared to 21.76 ± 3.88% in controls). Everolimus treatment also induced a significant decrease in Ki67 index and in the phosphorylation levels of the two major effectors of mTOR, p70S6K and 4E-BP1.

Conclusion: Our experimental data suggest that mTOR inhibition could be considered a therapeutic option for high-grade gastroenteropancreatic neuroendocrine tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Cell Line, Tumor
  • Everolimus
  • Female
  • Humans
  • Intestinal Neoplasms / drug therapy*
  • Intestinal Neoplasms / metabolism
  • Intestinal Neoplasms / pathology
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • Neuroendocrine Tumors / drug therapy*
  • Neuroendocrine Tumors / metabolism
  • Neuroendocrine Tumors / pathology
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Sirolimus / analogs & derivatives*
  • Sirolimus / therapeutic use
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology
  • TOR Serine-Threonine Kinases / metabolism
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Everolimus
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Sirolimus

Supplementary concepts

  • Gastro-enteropancreatic neuroendocrine tumor