Glioblastoma is a
primary brain tumor associated with a poor prognosis due to its high chemoresistance capacity. Cancer stem cells (CSCs) are one of the mechanisms of chemoresistance. Although
therapy targeting CSCs is promising, strategies targeting CSCs remain unsuccessful. Abnormal activation of
epidermal growth factor receptors (EGFRs) due to amplification, mutation, or both of the EGFR gene is common in
glioblastomas. However,
glioblastomas are resistant to EGFR
tyrosine kinase inhibitors (EGFR-TKIs), and overcoming resistance is essential.
Brexpiprazole is a new, safe
serotonin-
dopamine activity modulator used for
schizophrenia and depression that was recently reported to have anti-CSC activity and function as a chemosensitizer. Here, we examined its chemosensitization effects on
osimertinib, a third-generation EGFR-TKI with an excellent safety profile, in
glioma stem cells (GSCs), which are CSCs of
glioblastoma.
Brexpiprazole treatment sensitized GSCs to
osimertinib and reduced the expression of
survivin, an antiapoptotic factor, and the pharmacological and genetic inhibition of
survivin mimicked the effects of
brexpiprazole. Moreover, co-treatment of
brexpiprazole and
osimertinib suppressed
tumor growth more efficiently than either drug alone without notable toxicity in vivo. This suggests that the combination of
brexpiprazole and
osimertinib is a potential therapeutic strategy for
glioblastoma by chemosensitizing GSCs through the downregulation of
survivin expression.