EGFR and mTOR as therapeutic targets in glioblastoma

Michael W Ronellenfitsch,Anna-Luisa Luger,Joachim P Steinbach

doi:10.18632/oncotarget.27094

Abstract

The quest for new and improved therapies for glioblastoma (GB) has been mostly unsuccessful in more than a decade despite significant efforts. The few exceptions include the optimization of classical alkylating chemotherapy by including lomustine in the first line regimen for GB with a methylated MGMT promoter and tumor treating fields. The GB signaling network has been well-characterized and genetic alterations resulting in activation of receptor tyrosine kinases and especially epidermal growth factor receptor (EGFR) and downstream mammalian target of rapamycin complex 1 (mTORC1) signaling were found in the majority of GBs. ...

Highlights

The quest for new and improved therapies for glioblastoma (GB) has been mostly unsuccessful in more than a decade despite significant efforts
Except for a theoretical compensatory Akt pathway activation or potential toxicity related undertreatment, no plausible mechanistic explanations have been offered, we could previously demonstrate that epidermal growth factor receptor (EGFR) and mammalian target of rapamycin complex 1 (mTORC1) are at the center of GB cell adaptive responses (Figure 1)
The activity of the EGFR-mTORC1 axis is pivotal for survival under starvation conditions, but on the other hand it promotes the neoplastic phenotype of GB cells

Summary

Introduction

The quest for new and improved therapies for glioblastoma (GB) has been mostly unsuccessful in more than a decade despite significant efforts. Www.oncotarget.com ribosomal protein S6 and phosphorylated mTOR itself, appeared to respond to pathway inhibition by the EGFR antibody nimotuzumab or the mTORC1 inhibitor temsirolimus [5, 6]. The perils of mTORC1 inhibitor treatment in unselected GB patient cohorts with a “one size fits all approach” have been demonstrated by the recently published RTOG 0913 trial, where mTOR inhibition had detrimental effects with reduced overall survival [7].

Results

Conclusion