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Brexpiprazole, a Serotonin-Dopamine Activity Modulator, Can Sensitize Glioma Stem Cells to Osimertinib, a

Shuhei Suzuki1,2, Masahiro Yamamoto3, Tomomi Sanomachi1,2

  • 1Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.

Cancers
|July 10, 2019
PubMed

Insights

Brexpiprazole enhances chemotherapy for glioblastoma by sensitizing cancer stem cells (CSCs) to osimertinib. This combination therapy reduces tumor growth by downregulating survivin, offering a promising new treatment strategy.

Area of Science:

  • Neuro-oncology
  • Cancer Stem Cell Biology
  • Pharmacology

Background:

  • Glioblastoma exhibits poor prognosis due to chemoresistance, partly mediated by cancer stem cells (CSCs).
  • Epidermal growth factor receptor (EGFR) dysregulation is common, but glioblastomas resist EGFR tyrosine kinase inhibitors (EGFR-TKIs).
  • Brexpiprazole, a serotonin-dopamine modulator, shows potential anti-CSC and chemosensitizing properties.

Purpose of the Study:

  • To investigate the chemosensitization effects of brexpiprazole on osimertinib in glioblastoma stem cells (GSCs).
  • To explore the underlying mechanism involving survivin expression.
  • To evaluate the efficacy and toxicity of the combination therapy in vivo.

Main Methods:

  • Treatment of GSCs with brexpiprazole and osimertinib.
  • Assessment of GSC chemosensitization and survivin expression.
  • Pharmacological and genetic inhibition of survivin.
  • In vivo tumor growth suppression studies.

Main Results:

  • Brexpiprazole sensitized GSCs to osimertinib.
  • Survivin expression was reduced by brexpiprazole; survivin inhibition mimicked brexpiprazole's effects.
  • Combined brexpiprazole and osimertinib suppressed glioblastoma tumor growth more effectively than monotherapy without significant toxicity.

Conclusions:

  • Brexpiprazole acts as a chemosensitizer for glioblastoma stem cells against EGFR-TKI treatment.
  • The combination of brexpiprazole and osimertinib represents a potential therapeutic strategy for glioblastoma.
  • Survivin downregulation is a key mechanism mediating the chemosensitization effect.
Keywords:
brexpiprazoleglioblastomaglioma stem cellosimertinibsurvivinxenograft

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