Divergent Roles of PI3K Isoforms in PTEN-Deficient Glioblastomas

Loss of PTEN, the negative regulator of PI3K activity, is frequent in glioblastomas (GBMs). However, the role of the two major PI3K isoforms, p110 alpha and p110 beta, in PTEN-deficient gliomagenesis remains unknown. We show that PTEN-deficient GBM largely depends on p110 alpha for proliferation and p110 beta for migration. Genetic ablation of either isoform delays tumor progression in mice, but only ablating both isoforms completely blocks GBM driven by the concurrent ablation of Pten and p53. BKM120 (buparlisib) treatment only modestly prolongs survival inmice bearing intracranial Pten/p53 null tumors due to partial pathway inhibition. BKM120 extends the survival of mice bearing intracranial tumors in which p110 beta, but not p110 alpha, has been genetically ablated in the Pten/p53 null glioma, indicating that BKM120 fails to inhibit p110 beta effectively. Our study suggests that the failure of PI3K inhibitors in GBM may be due to insufficient inhibition of p110 beta and indicates a need to develop brain- penetrant p110 alpha/beta inhibitors.