A Dual Phosphoinositide-3-Kinase α/mTOR Inhibitor Cooperates with Blockade of Epidermal Growth Factor Receptor in PTEN-Mutant Glioma
QW Fan, CK Cheng, TP Nicolaides, CS Hackett… - Cancer research, 2007 - AACR
Cancer research, 2007•AACR
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 PI3Kα 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 …
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 PI3Kα 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 …
Abstract
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 PI3Kα and mTOR (PI-103). Erlotinib blocked proliferation only in PTENwt cells expressing EGFR. Although erlotinib monotherapy showed little effect in PTENmt glioma, PI-103 greatly augmented the antiproliferative efficacy of erlotinib in this setting. To address the importance of PI3K blockade, we showed in PTENmt 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 PI3Kα). These experiments show that a dual inhibitor of PI3Kα and mTOR augments the activity of EGFR blockade, offering a mechanistic rationale for targeting EGFR, PI3Kα, and mTOR in the treatment of EGFR-driven, PTEN-mutant glioma. [Cancer Res 2007;67(17):7960–5]
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