mTOR Inhibition Leads to Src-Mediated EGFR Internalisation and Degradation in Glioma Cells

Abstract

Epidermal Growth Factor receptor (EGFR) is a tyrosine kinase receptor widely expressed on the surface of numerous cell types, which activates several downstream signalling pathways involved in cell proliferation, migration and survival. EGFR alterations, such as overexpression or mutations, have been frequently observed in several cancers, including glioblastoma (GBM), and are associated to uncontrolled cell proliferation. Here we show that the inhibition of mammalian target of Rapamycin (mTOR) mediates EGFR delivery to lysosomes for degradation in GBM cells, independently of autophagy activation. Coherently with EGFR internalisation and degradation, mTOR blockade negatively affects the mitogen activated protein/extracellular signal-regulated kinase (MAPK)/ERK pathway. Furthermore, we provide evidence that Src kinase activation is required for EGFR internaliation upon mTOR inhibition. Our results further support the hypothesis that mTOR targeting may represent an effective therapeutic strategy in GBM management, as its inhibition results in EGFR degradation and in proliferative signal alteration.

Targeting RTK-PI3K-mTOR Axis in Gliomas: An Update

“…Intriguingly, we recently demonstrated a peculiar feedback loop between mTOR inhibition and RTKs trafficking/expression. Chiefly, the mTOR inhibitors Torin1 and AZD8055 can induce EGFR internalization and lysosomal delivery in GBM cells via an Src-dependent mechanism ( Figure 2 ) [ 54 ]. EGFR delocalization is accompanied by ERK1/2 inactivation, which is likely responsible for a substantial reduction of cell proliferation and the potentiation of the antiproliferative effect of TMZ [ 54 ].…”

“…Chiefly, the mTOR inhibitors Torin1 and AZD8055 can induce EGFR internalization and lysosomal delivery in GBM cells via an Src-dependent mechanism ( Figure 2 ) [ 54 ]. EGFR delocalization is accompanied by ERK1/2 inactivation, which is likely responsible for a substantial reduction of cell proliferation and the potentiation of the antiproliferative effect of TMZ [ 54 ]. These results, together with previous evidence showing an mTOR-dependent impairment in invasion capabilities of GBM cells [ 122 ], suggest that the effects of mTOR inhibition can be further exploited to counteract glioma proliferation, migration, and invasion.…”

“…In GBMs, autophagy induced by TMZ is thought of as a survival and protective mechanism, and is generally considered as a mechanism of chemoresistance [ 53 ]. However, we recently demonstrated that mTOR inhibition, and in turn, autophagy induction potentiate the antiproliferative effect of TMZ in GBM models [ 54 ]. Therefore, further studies are necessary to dissect the role played by mTOR and autophagy on TMZ response.…”

“…In this regard, we have recently shown that Torin1 can inhibit cell proliferation and sensitize GBM cells to TMZ in in vitro experiments [ 54 ]. The antiproliferative effect of Torin1 is likely mediated by ERK1/2 downregulation, which could be the consequence of the observed impairment of EGFR recycling to the cell surface [ 54 ] ( Figure 2 ).…”

“…In this regard, we have recently shown that Torin1 can inhibit cell proliferation and sensitize GBM cells to TMZ in in vitro experiments [ 54 ]. The antiproliferative effect of Torin1 is likely mediated by ERK1/2 downregulation, which could be the consequence of the observed impairment of EGFR recycling to the cell surface [ 54 ] ( Figure 2 ). In previous studies, we also demonstrated that both Torin1 and Rapamycin can impair cell migration and invasion, by reverting the EMT process and by impinging the Wnt/β-catenin pathway in GBM cells [ 122 , 123 ].…”