Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 16; pp. 7864 - 7869
• Main Authors: WANG, Maria Y, LU, Kan V, MISCHEL, Paul S, SHAOJUN ZHU, DIA, Ederlyn Q, VIVANCO, Igor, SHACKLEFORD, Gregory M, CAVENEE, Webster K, MELLINGHOFF, Ingo K, CLOUGHESY, Timothy F, SAWYERS, Charles L
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.08.2006
• Subjects: Antineoplastic agents; Biological and medical sciences; Cell Division - drug effects; Cell Line, Tumor; Enzyme Activation; Erlotinib Hydrochloride; Glioblastoma - genetics; Glioblastoma - pathology; Humans; Medical sciences; Neurology; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Kinases - physiology; PTEN Phosphohydrolase - deficiency; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Sirolimus - pharmacology; TOR Serine-Threonine Kinases; Transfection; Tumors; Tumors of the nervous system. Phacomatoses; Protein kinase mTOR; Nervous system diseases; Enzyme; Transferases; Glioblastoma; Malignant tumor; In vitro; Epidermal growth factor receptor; Malignant glioma; Growth factor receptor; Kinase; Central nervous system disease; PTEN Gene; Inhibitor; Tumor suppressor gene
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-04-4392

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 PTEN-deficient 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.