A dual phosphoinositide-3-kinase α/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma

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 alpha 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 PI3K alpha.). These experiments show that a dual inhibitor of PI3K alpha, and mTOR augments the activity of EGFR blockade, offering a mechanistic rationale for targeting EGFR, PI3K alpha, and mTOR in the treatment of EGFR-driven, PTEN-mutant glioma.