Mammalian Target of Rapamycin Inhibition Promotes Response to Epidermal Growth Factor Receptor Kinase Inhibitors in PTEN-Deficient and PTEN-Intact Glioblastoma Cells

Abstract

The epidermal growth factor receptor (EGFR) is commonly amplified, overexpressed, and mutated in glioblastoma, making it a compelling molecular target for therapy. We have recently shown that coexpression of EGFRvIII and PTEN protein by glioblastoma cells is strongly associated with clinical response to EGFR kinase inhibitor therapy. PTEN loss, by dissociating inhibition of the EGFR from downstream phosphatidylinositol 3-kinase (PI3K) pathway inhibition, seems to act as a resistance factor. Because 40% to 50% of glioblastomas are PTEN deficient, a critical challenge is to identify strategies that promote responsiveness to EGFR kinase inhibitors in patients whose tumors lack PTEN. Here, we show that the mammalian target of rapamycin (mTOR) inhibitor rapamycin enhances the sensitivity of PTENdeficient tumor cells to the EGFR kinase inhibitor erlotinib. In two isogenic model systems (U87MG glioblastoma cells expressing EGFR, EGFRvIII, and PTEN in relevant combinations, and SF295 glioblastoma cells in which PTEN protein expression has been stably restored), we show that combined EGFR/mTOR kinase inhibition inhibits tumor cell growth and has an additive effect on inhibiting downstream PI3K pathway signaling. We also show that combination therapy provides added benefit in promoting cell death in PTEN-deficient tumor cells. These studies provide strong rationale for combined mTOR/EGFR kinase inhibitor therapy in glioblastoma patients, particularly those with PTEN-deficient tumors.

Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs

“…These evidences support the hypothesis that a more efficient antitumour effect may result from the combined blockade of EGFR and mTOR signalling pathways. Preclinical evidences demonstrate that this approach may be particularly effective, at least in some experimental models in which the combination of EGFR antagonists, such as gefitinib or erlotinib, and mTOR inhibitors, such as rapamycin and everolimus, resulted in an enhanced tumour cell growth control (Gemmill et al, 2005;Goudar et al, 2005;Rao et al, 2005;Wang et al, 2006;Jimeno et al, 2007). Recently, a pilot study including 28 heavily pretreated patients with recurrent malignant gliomas treated with the combination of gefitinib or erlotinib and rapamycin reported interesting results in terms of toxicity and tumour response (Doherty et al, 2006).…”

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

“…3 Similarly, it promotes resistance to EGFR tyrosine kinase inhibitors in glioblastoma, colon, and lung cancer. [4][5][6] In gastrointestinal stromal tumors (GISTs), KIT and PDGFRA are fundamental therapeutic targets; however, the majority of GIST patients eventually develop resistance to imatinib mesylate and to other receptor tyrosine kinase inhibitors currently applied in the clinic. 7 This resistance is mainly due to the re-activation of KIT signaling by the acquisition of secondary KIT mutations.…”

Therapeutic Inhibition of the Epidermal Growth Factor Receptor in High-Grade Gliomas: Where Do We Stand?

“…PTEN-deficient U87 and SF295 glioblastoma cells exposed to combined treatment with erlotinib and rapamycin, an mTOR inhibitor, showed significantly increased antiproliferative effects when compared with cells receiving erlotinib alone (112). A 38% reduction in proliferation was observed for PTEN-deficient SF295 cells treated with erlotinib and rapamycin versus 14% on treatment with erlotinib alone.…”

“…In experimental studies, increased antineoplastic effects were obtained when therapeutics were combined to target oncogenic signal transduction at various levels. In PTEN-deficient cells, additional inhibition of downstream signaling using rapamycin to inhibit mTOR was shown to significantly improve therapeutic response (112). In a first phase I study, a combinatorial regimen of gefitinib and sirolimus was applied to patients with recurrent glioblastoma (79).…”