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A Dual Phosphoinositide-3-Kinase /mTOR Inhibitor Cooperates with Blockade of Epidermal Growth Factor Receptor in PTEN-Mutant Glioma

Departments of ¹ Neurology, ² Pediatrics, ³ Neurological Surgery and Brain Tumor Research Center, ⁴ Comprehensive Cancer Center, ⁵ Biomedical Sciences Graduate Program, ⁶ Program in Chemistry and Chemical Biology, ⁷ Cellular and Molecular Pharmacology, and ⁸ Howard Hughes Medical Institute, University of California, San Francisco, California

Requests for reprints: Qi-Wen Fan, Neurology, Room U441K, University of California at San Francisco, 533 Parnassus Avenue, San Francisco, CA 94143. Phone: 415-502-1695; Fax: 415-476-0133; E-mail: QiWen.fan{at}ucsf.edu.

We have shown previously that blockade of epidermal growth factor receptor (EGFR) cooperates with a pan-selective inhibitor of phosphoinositide-3-kinase (PI3K) in EGFR-driven glioma. In this communication, we tested EGFR-driven glioma differing in PTEN status, treating with the EGFR inhibitor erlotinib and a novel dual inhibitor of PI3K and mTOR (PI-103). Erlotinib blocked proliferation only in PTEN^wt cells expressing EGFR. Although erlotinib monotherapy showed little effect in PTEN^mt glioma, PI-103 greatly augmented the antiproliferative efficacy of erlotinib in this setting. To address the importance of PI3K blockade, we showed in PTEN^mt glioma that combining PI-103 and erlotinib was superior to either monotherapy or to therapy combining erlotinib with either rapamycin (an inhibitor of mTOR) or PIK-90 (an inhibitor of PI3K). These experiments show that a dual inhibitor of PI3K and mTOR augments the activity of EGFR blockade, offering a mechanistic rationale for targeting EGFR, PI3K, and mTOR in the treatment of EGFR-driven, PTEN-mutant glioma. [Cancer Res 2007;67(17):7960–5]

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