A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma

Cancer Res. 2007 Sep 1;67(17):7960-5. doi: 10.1158/0008-5472.CAN-07-2154.

Abstract

We have shown previously that blockade of epidermal growth factor receptor (EGFR) cooperates with a pan-selective inhibitor of phosphoinositide-3-kinase (PI3K) in EGFR-driven glioma. In this communication, we tested EGFR-driven glioma differing in PTEN status, treating with the EGFR inhibitor erlotinib and a novel dual inhibitor of PI3Kalpha and mTOR (PI-103). Erlotinib blocked proliferation only in PTEN(wt) cells expressing EGFR. Although erlotinib monotherapy showed little effect in PTEN(mt) glioma, PI-103 greatly augmented the antiproliferative efficacy of erlotinib in this setting. To address the importance of PI3K blockade, we showed in PTEN(mt) glioma that combining PI-103 and erlotinib was superior to either monotherapy or to therapy combining erlotinib with either rapamycin (an inhibitor of mTOR) or PIK-90 (an inhibitor of PI3Kalpha). These experiments show that a dual inhibitor of PI3Kalpha and mTOR augments the activity of EGFR blockade, offering a mechanistic rationale for targeting EGFR, PI3Kalpha, and mTOR in the treatment of EGFR-driven, PTEN-mutant glioma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cell Cycle / drug effects
  • Drug Evaluation, Preclinical
  • Drug Synergism
  • ErbB Receptors / antagonists & inhibitors*
  • Erlotinib Hydrochloride
  • Furans / administration & dosage
  • Furans / pharmacology*
  • Glioma / drug therapy*
  • Glioma / genetics
  • Glioma / pathology
  • Humans
  • PTEN Phosphohydrolase / genetics*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinases / drug effects*
  • Pyridines / administration & dosage
  • Pyridines / pharmacology*
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacology*
  • Quinazolines / administration & dosage
  • Quinazolines / pharmacology*
  • TOR Serine-Threonine Kinases
  • Treatment Outcome
  • Tumor Cells, Cultured

Substances

  • Furans
  • PI103
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • Quinazolines
  • Erlotinib Hydrochloride
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • ErbB Receptors
  • PTEN Phosphohydrolase
  • PTEN protein, human