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Divergent Roles of PI3K Isoforms in PTEN-Deficient Glioblastomas

Shaozhen Xie1, Jing Ni1, J Ricardo McFaline-Figueroa2

  • 1Department 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.

Cell Reports
|September 30, 2020
PubMed

Insights

Loss of PTEN in glioblastoma (GBM) often leads to cancer driven by PI3K isoforms p110α and p110β. Inhibiting both isoforms is crucial, as current drugs inadequately target p110β, hindering GBM treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Loss of PTEN, a key negative regulator of PI3K signaling, is common in glioblastomas (GBMs).
  • The distinct roles of PI3K isoforms p110α and p110β in PTEN-deficient gliomagenesis are not well understood.
  • Understanding these roles is critical for developing effective GBM therapies.

Purpose of the Study:

  • To investigate the specific contributions of PI3K isoforms p110α and p110β to PTEN-deficient glioblastoma development.
  • To evaluate the efficacy of PI3K inhibition in preclinical GBM models.
  • To identify potential therapeutic strategies targeting PI3K signaling in GBM.

Main Methods:

  • Genetic ablation of PI3K isoforms p110α and p110β in mouse models of PTEN- and p53-deficient glioblastoma.
  • Assessment of tumor proliferation and migration following isoform-specific genetic manipulation.
  • Pharmacological inhibition using BKM120 (buparlisib) and evaluation of its impact on tumor progression and survival.
  • Analysis of PI3K pathway inhibition by BKM120 in relation to specific isoform ablation.

Main Results:

  • PTEN-deficient GBM exhibits differential dependence on PI3K isoforms, with p110α driving proliferation and p110β driving migration.
  • Genetic ablation of either p110α or p110β individually delays GBM progression in mice.
  • Complete blockade of GBM requires concurrent ablation of both p110α and p110β in Pten/p53 null models.
  • BKM120 treatment provides only modest survival benefits in established Pten/p53 null GBMs due to incomplete pathway inhibition.
  • BKM120 efficacy is limited in tumors with intact p110β, suggesting insufficient inhibition of this isoform.

Conclusions:

  • PI3K isoforms p110α and p110β play distinct and critical roles in PTEN-deficient glioblastoma.
  • Targeting both p110α and p110β simultaneously is necessary for complete tumor suppression.
  • Current PI3K inhibitors like BKM120 may be ineffective due to insufficient inhibition of the p110β isoform.
  • Development of novel, brain-penetrant inhibitors targeting both p110α and p110β is warranted for effective GBM treatment.
Keywords:
BKM120BYL719GEMMPDXPI3K isoformPTENPTEN-deficientglioblastomaisoform-selective inhibitormigration

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