Abstract
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.
Highlights
Glioblastoma is the most common primary brain tumor, accounting for 60% to 70% of glial brain tumors [1,2]
EGFRvIII lacks a major part of the extracellular domain and is constitutively active [12,13]; EGFRvIII plays a role in the progression of glioblastoma [10,11,14]
As the presence of EGFRvIII mutations may affect the sensitivity of osimertinib, we examined the expression of EGFRvIII in these cells
Summary
Glioblastoma is the most common primary brain tumor, accounting for 60% to 70% of glial brain tumors [1,2]. The outcome of glioblastoma is poor due to its highly infiltrative growth and high chemoresistance to therapeutic agents such as temozolomide [3,4]. Cancer stem cells (CSCs), which have high tumor initiation capacity and are resistant to chemotherapeutic reagents, play a role in chemoresistance [5,6,7,8]. The development of drugs eradicating glioma stem cells (GSCs), CSCs of glioblastoma, is important for the treatment of glioblastoma. Cancers 2019, 11, 947 for glioblastoma is limited because drugs that poorly penetrate the blood–brain barrier (BBB) are not effective for glioblastoma [9]. 50% of EGFR-amplified glioblastomas express epidermal growth factor receptor (EGFR) variant III (EGFRvIII) resulting from the in-frame deletion of exons 2–7. EGFRvIII lacks a major part of the extracellular domain and is constitutively active [12,13]; EGFRvIII plays a role in the progression of glioblastoma [10,11,14]
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