Research ArticleBRAIN TUMORS

BCL3 expression promotes resistance to alkylating chemotherapy in gliomas

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Science Translational Medicine  04 Jul 2018:
Vol. 10, Issue 448, eaar2238
DOI: 10.1126/scitranslmed.aar2238

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BCL3 dampens drug efficacy in gliomas

Chemotherapy with alkylating agents, including temozolomide (TMZ), is the most effective treatment for gliomas, but many patients do not respond to the treatment. Wu et al. now report that high B cell CLL/lymphoma 3 (BCL3) expression promoted resistance to TMZ by activating carbonic anhydrase II. Patients with high BCL3-expressing gliomas showed a poorer response to TMZ and shorter survival than did patients with low BCL3-expressing gliomas. In mice injected with high BCL3-expressing human gliomas, the carbonic anhydrase II inhibitor acetazolamide increased sensitivity to TMZ and survival in the mouse xenograft model. The results suggest that analysis of BCL3 expression might be useful in determining the best therapy for treating gliomas.

Abstract

The response of patients with gliomas to alkylating chemotherapy is heterogeneous. However, there are currently no universally accepted predictors of patient response to these agents. We identify the nuclear factor κB (NF-κB) co-regulator B cell CLL/lymphoma 3 (BCL-3) as an independent predictor of response to temozolomide (TMZ) treatment. In glioma patients with tumors that have a methylated O6-methylguanine DNA methyltransferase (MGMT) promoter, high BCL-3 expression was associated with a poor response to TMZ. Mechanistically, BCL-3 promoted a more malignant phenotype by inducing an epithelial-to-mesenchymal transition in glioblastomas through promoter-specific NF-κB dimer exchange. Carbonic anhydrase II (CAII) was identified as a downstream factor promoting BCL-3–mediated resistance to chemotherapy. Experiments in glioma xenograft mouse models demonstrated that the CAII inhibitor acetazolamide enhanced survival of TMZ-treated animals. Our data suggest that BCL-3 might be a useful indicator of glioma response to alkylating chemotherapy and that acetazolamide might be repurposed as a chemosensitizer for treating TMZ-resistant gliomas.

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