Divergent Roles of PI3K Isoforms in PTEN-Deficient Glioblastomas.

ABSTRACT: Loss of PTEN, the negative regulator of PI3K activity, is frequent in glioblastomas (GBMs). However, the role of the two major PI3K isoforms, p110? and p110?, in PTEN-deficient gliomagenesis remains unknown. We show that PTEN-deficient GBM largely depends on p110? for proliferation and p110? 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 in mice bearing intracranial Pten/p53 null tumors due to partial pathway inhibition. BKM120 extends the survival of mice bearing intracranial tumors in which p110?, but not p110?, has been genetically ablated in the Pten/p53 null glioma, indicating that BKM120 fails to inhibit p110? effectively. Our study suggests that the failure of PI3K inhibitors in GBM may be due to insufficient inhibition of p110? and indicates a need to develop brain-penetrant p110?/? inhibitors.

SUBMITTER: Xie S 

PROVIDER: S-EPMC7571617 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature