2. Academic Validation
  3. Divergent Roles of PI3K Isoforms in PTEN-Deficient Glioblastomas

Divergent Roles of PI3K Isoforms in PTEN-Deficient Glioblastomas

  • Cell Rep. 2020 Sep 29;32(13):108196. doi: 10.1016/j.celrep.2020.108196.
Shaozhen Xie 1,  Jing Ni 1,  J Ricardo McFaline-Figueroa 2,  Yanzhi Wang 3,  Roderick T Bronson 4,  Keith L Ligon 5,  Patrick Y Wen 5,  Thomas M Roberts 6,  Jean J Zhao 7
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Medical Oncology and Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 4 Dana-Farber/Harvard Cancer Center Rodent Histopathology Core, Boston, MA 02215, USA.
  • 5 Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Medical Oncology and Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 6 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA. Electronic address: [email protected].
  • 7 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: [email protected].
PMID: 32997991 DOI: 10.1016/j.celrep.2020.108196
Abstract

Loss of PTEN, the negative regulator of PI3K activity, is frequent in glioblastomas (GBMs). However, the role of the two major PI3K isoforms, p110α and p110β, in PTEN-deficient gliomagenesis remains unknown. We show that PTEN-deficient GBM largely depends on p110α for proliferation and p110β 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 p110β, but not p110α, has been genetically ablated in the PTEN/p53 null glioma, indicating that BKM120 fails to inhibit p110β effectively. Our study suggests that the failure of PI3K inhibitors in GBM may be due to insufficient inhibition of p110β and indicates a need to develop brain-penetrant p110α/β inhibitors.

Keywords

BKM120; BYL719; GEMM; PDX; PI3K isoform; PTEN; PTEN-deficient; glioblastoma; isoform-selective inhibitor; migration.

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