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Selective Inhibition of PI3K Isoforms in Brain Tumors Suppresses Tumor Growth by Increasing Radiosensitivity

Mi Youn Seol1, Seo Hee Choi1,2, Ik Jae Lee1

  • 1Department of Radiation Oncology, Yonsei Cancer Center, Heavy Ion Therapy Research Institute, Yonsei University College of Medicine, Seoul, Korea.

Yonsei Medical Journal
|January 31, 2023
PubMed
Abstract

Insights

Targeting the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway with PI3K-alpha inhibitors enhances radiosensitivity in glioblastoma (GBM). This combination therapy suppresses tumor growth and extends survival in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Radiotherapy

Background:

  • Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options.
  • Tumor radioresistance is a significant clinical challenge, hindering effective radiotherapy outcomes.
  • The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway is implicated in GBM development and promotes radioresistance.

Purpose of the Study:

  • To investigate the potential of selective PI3K isoform inhibitors to overcome radioresistance in GBM.
  • To evaluate the efficacy of combining radiotherapy with PI3K isoform inhibitors in GBM treatment.

Main Methods:

  • In vitro studies using GL261-luc and LN229 cells assessed cell viability (clonogenic assay) and pathway inhibition (Western blot).
  • Radiosensitivity was confirmed by observing phospho-γ-H2AX expression via immunofluorescence.
  • An in vivo intracranial mouse model (GL261-luc) evaluated tumor growth (IVIS imaging) and survival (Kaplan-Meier curves) with PI3K-α inhibition and radiation.

Main Results:

  • Inhibition of the PI3K/AKT pathway enhanced radiosensitivity in GBM cells.
  • PI3K-α isoform inhibition demonstrated comparable effects to pan-PI3K inhibition in vitro.
  • Combination therapy of radiotherapy and PI3K-α inhibitor significantly suppressed tumor growth and prolonged survival in vivo.

Conclusions:

  • Selective PI3K-α isoform inhibition is a promising strategy to improve GBM radiosensitivity.
  • This approach leads to reduced tumor progression and enhanced survival in preclinical GBM models.
  • Targeting PI3K-α offers a potential therapeutic avenue to improve GBM patient outcomes.
Keywords:
GlioblastomaPI3K-isoformradiationradioresistanceradiosensitivity

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