Disruption of parallel and converging signaling pathways contributes to the synergistic antitumor effects of simultaneous mTOR and EGFR inhibition in GBM cells

Ravi D. Rao, Ann C. Mladek, Jeffrey D. Lamont, Jennie M. Goble, Charles Erlichman, C. David James, Jann N Sarkaria

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Elevated epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) signaling are known to contribute to the malignant properties of glioblastoma multiforme (GBM), which include uncontrolled cell proliferation and evasion of apoptosis. Small molecule inhibitors that target these protein kinases have been evaluated in multiple clinical trials for cancer patients, including those with GBM. Here we have examined the cellular and molecular effects of a combined kinase inhibition of mTOR (rapamycin) and EGFR (EKI-785) in U87 and U251 GBM cells. Simultaneous treatment with rapamycin and EKI-785 results in synergistic antiproliferative as well as proapoptotic effects. At a molecular level, rapamycin alone significantly decreases S6 phosphorylation, whereas EKI-785 alone promotes substantially reduced signal transducer and activator of transcription (STAT3) phosphorylation. Treatment with rapamycin alone also increases Akt phosphorylation on Ser-473, but this effect is blocked by a simultaneous administration of EKI-785. Individually, EKI-785 diminishes while rapamycin promotes the binding of the translation inhibitor eukaryotic initiation factor 4E binding protein (4EBP1) to the eukaryotic translation initiation factor 4E (eIF4E). In spite of these opposing effects, the highest level of 4EBP1-eIF4E binding occurs with the combination of the two inhibitors. These results indicate that the inhibition of EGFR and mTOR has distinct as well as common signaling consequences and provides a molecular rationale for the synergistic antitumor effects of EKI-785 and rapamycin administration.

Original languageEnglish (US)
Pages (from-to)921-929
Number of pages9
JournalNeoplasia
Volume7
Issue number10
DOIs
StatePublished - Oct 2005

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Sirolimus
Glioblastoma
Epidermal Growth Factor Receptor
Eukaryotic Initiation Factor-4E
Eukaryotic Initiation Factors
Phosphorylation
S 6
Protein Kinase Inhibitors
Transducers
EKI 785
Carrier Proteins
Phosphotransferases
Cell Proliferation
Clinical Trials
Apoptosis
Therapeutics

Keywords

  • 4EBP1
  • Akt
  • Epidermal growth factor receptor
  • Glioblastoma
  • Rapamycin
  • Signal transduction

ASJC Scopus subject areas

  • Cancer Research

Cite this

Disruption of parallel and converging signaling pathways contributes to the synergistic antitumor effects of simultaneous mTOR and EGFR inhibition in GBM cells. / Rao, Ravi D.; Mladek, Ann C.; Lamont, Jeffrey D.; Goble, Jennie M.; Erlichman, Charles; James, C. David; Sarkaria, Jann N.

In: Neoplasia, Vol. 7, No. 10, 10.2005, p. 921-929.

Research output: Contribution to journalArticle

Rao, Ravi D. ; Mladek, Ann C. ; Lamont, Jeffrey D. ; Goble, Jennie M. ; Erlichman, Charles ; James, C. David ; Sarkaria, Jann N. / Disruption of parallel and converging signaling pathways contributes to the synergistic antitumor effects of simultaneous mTOR and EGFR inhibition in GBM cells. In: Neoplasia. 2005 ; Vol. 7, No. 10. pp. 921-929.
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