['The PI3K-AKT-mTOR signaling pathway is frequently activated in glioblastoma (GBM) and offers several drugable targets. However, clinical efficacy of PI3K/mTOR inhibitors in GBM has not yet been demonstrated. Insufficient drug delivery may limit the efficacy of PI3K/mTOR inhibitors against GBM. The presence of the efflux transporters ABCB1/Abcb1 (P-glycoprotein, MDR1) and ABCG2/Abcg2 (BCRP) at the blood-brain barrier (BBB) restricts the brain penetration of many drugs.', 'We used in vitro drug transport assays and performed pharmacokinetic/pharmacodynamic studies in wildtype and ABC-transporter knockout mice.. The efficacy of PI3K-mTOR inhibition was established using orthotopic allograft and genetically engineered spontaneous glioblastoma mouse models.', 'The mTOR inhibitors rapamycin and AZD8055 are substrates of ABCB1 whereas the dual PI3K/mTOR inhibitor NVP-BEZ235 and the PI3K inhibitor ZSTK474 are not. Moreover, ABCG2 transports NVP-BEZ235 and AZD8055 but not ZSTK474 or rapamycin. Concordantly, Abcb1a/b-/-;Abcg2-/- mice revealed increased brain penetration of rapamycin (13-fold), AZD8055 (7.7-fold) and NVP-BEZ235 (4.5-fold) but not ZSTK474 relative to WT mice. Importantly, ABC-transporters limited rapamycin brain penetration to sub-therapeutic levels, while the reduction in NVP-BEZ235 brain penetration did not prevent target inhibition. NVP-BEZ235 and ZSTK474 demonstrated antitumor efficacy with improved survival against U87 orthotopic gliomas, although the effect of ZSTK474 was more pronounced. Lastly, ZSTK474 prolonged overall survival in Cre-LoxP conditional transgenic Pten;p16Ink4a/p19Arf;K-Rasv12;LucR mice, mainly by delaying tumor onset.'] Does pI3K-mTOR pathway inhibition exhibit efficacy against high-grade glioma in clinically relevant mouse models?