Research ArticleCancer

Ibrutinib inactivates BMX-STAT3 in glioma stem cells to impair malignant growth and radioresistance

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Science Translational Medicine  30 May 2018:
Vol. 10, Issue 443, eaah6816
DOI: 10.1126/scitranslmed.aah6816

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Stemming the tide of glioblastoma growth

Glioblastoma is a lethal and difficult to treat primary brain tumor. Similar to many cancers, glioblastoma contains a population of stem cells, which are particularly treatment-resistant and promote tumor growth. A protein called bone marrow and X-linked (BMX) nonreceptor tyrosine kinase is active in these cells and can be targeted with ibrutinib, an approved drug used in other cancers. Shi et al. demonstrated that ibrutinib specifically targets glioma stem cells but not healthy neural stem cells, which do not express BMX, and demonstrated the effectiveness and safety of ibrutinib treatment in mouse models.

Abstract

Glioblastoma (GBM) is the most lethal primary brain tumor and is highly resistant to current treatments. GBM harbors glioma stem cells (GSCs) that not only initiate and maintain malignant growth but also promote therapeutic resistance including radioresistance. Thus, targeting GSCs is critical for overcoming the resistance to improve GBM treatment. Because the bone marrow and X-linked (BMX) nonreceptor tyrosine kinase is preferentially up-regulated in GSCs relative to nonstem tumor cells and the BMX-mediated activation of the signal transducer and activator of transcription 3 (STAT3) is required for maintaining GSC self-renewal and tumorigenic potential, pharmacological inhibition of BMX may suppress GBM growth and reduce therapeutic resistance. We demonstrate that BMX inhibition by ibrutinib potently disrupts GSCs, suppresses GBM malignant growth, and effectively combines with radiotherapy. Ibrutinib markedly disrupts the BMX-mediated STAT3 activation in GSCs but shows minimal effect on neural progenitor cells (NPCs) lacking BMX expression. Mechanistically, BMX bypasses the suppressor of cytokine signaling 3 (SOCS3)–mediated inhibition of Janus kinase 2 (JAK2), whereas NPCs dampen the JAK2-mediated STAT3 activation via the negative regulation by SOCS3, providing a molecular basis for targeting BMX by ibrutinib to specifically eliminate GSCs while preserving NPCs. Our preclinical data suggest that repurposing ibrutinib for targeting GSCs could effectively control GBM tumor growth both as monotherapy and as adjuvant with conventional therapies.

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