PI3K/PTEN/Akt pathway status affects the sensitivity of high-grade glioma cell cultures to the insulin-like growth factor-1 receptor inhibitor NVP-AEW541

Neuro Oncol. 2010 Sep;12(9):967-75. doi: 10.1093/neuonc/noq029. Epub 2010 Apr 8.


IGF-1 receptor signaling contributes to the growth of many solid tumors, including glioblastoma. This study analyzed the sensitivity of 8 glioblastoma cultures to the IGF-1 receptor inhibitor NVP-AEW541. Growth reduction, caused by a combination of antiproliferative and proapoptotic effects, varied between 20% and 100%. Growth-inhibitory effects of IGF-1 receptor siRNA were also demonstrated in 2 of the cultures. Activating mutations in PIK3CA were found in 2 cultures, and 2 other cultures displayed ligand-independent Akt phosphorylation. Growth inhibition was significantly reduced in cultures with PIK3CA mutations or ligand-independent Akt phosphorylation. PTEN siRNA experiments supported the notion that the status of the PI3K/PTEN/Akt pathway is involved in determining NVP-AEW541 sensitivity. Combination treatments with either PI3 kinase or mTOR inhibitors together with NVP-AEW541 were performed. These experiments demonstrated the effects of NVP-AEW541 in cells not responding to mono-treatment with the IGF-1 receptor inhibitor, when used together with either of the 2 other inhibitors. Together, the studies support continued clinical development of IGF-1 receptor antagonists for glioblastomas and identify links between PI3K/PTEN/Akt status and sensitivity to mono-treatment with NVP-AEW541. Furthermore, the studies suggest that NVP-AEW541 is also active together with PI3 kinase and mTOR inhibitors in cultures with a dysregulated PI3K/PTEN/Akt pathway. These studies should assist in future clinical development of IGF-1 receptor antagonists for glioblastoma and other tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm / physiology*
  • Glioma / metabolism*
  • Humans
  • Immunoblotting
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrimidines / pharmacology*
  • Pyrroles / pharmacology*
  • RNA, Small Interfering
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*


  • Antineoplastic Agents
  • NVP-AEW541
  • Pyrimidines
  • Pyrroles
  • RNA, Small Interfering
  • Phosphatidylinositol 3-Kinases
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase