γ-Secretase inhibitor-resistant glioblastoma stem cells require RBPJ to propagate.
Targeting glioblastoma stem cells with γ-secretase inhibitors (GSIs) disrupts the Notch pathway and has shown some benefit in both pre-clinical models and in patients during phase I/II clinical trials. However, it is largely unknown why some glioblastoma (GBM) does not respond to GSI treatment. In this issue of the JCI, Xie et al. determined that GSI-resistant brain tumor-initiating cells (BTICs) from GBM express a higher level of the gene RBPJ, which encodes a mediator of canonical Notch signaling, compared to non-BTICs. Knockdown of RBPJ in BTICs decreased propagation in vitro and in vivo by inducing apoptosis. Interestingly, RBPJ was shown to regulate a different transcription program than Notch in BTICs by binding CDK9, thereby affecting Pol II-regulated transcript elongation. Targeting CDK9 or c-MYC, an upstream regulator of RBPJ, with small molecules also decreased BTIC propagation, and prolonged survival in mice bearing orthotopic GBM xenografts. This study not only provides a mechanism for GSI treatment resistance, but also identifies two potential therapeutic strategies to target GSI-resistant BTICs.
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D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D001932:Brain Neoplasms; D049109:Cell Proliferation; D005909:Glioblastoma; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells; D051880:Receptors, Notch; D015398:Signal Transduction
D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases