Combined HDAC and Bromodomain Protein Inhibition Reprograms Tumor Cell Metabolism and elicits Synthetic Lethality in Glioblastoma

Purpose: Glioblastoma remain a challenge in oncology in part due to tumor heterogeneity. Experimental Design: Patient-derived xenograft and stem-like glioblastoma cells were used as the primary model systems. Results: Based on a transcriptome and subsequent gene set enrichment analysis (GSEA), we show by using clinically validated compounds that combined histone deacetylase (HDAC) inhibition and Bromodomain protein (BRD) inhibition results in pronounced synergistic reduction in cellular viability in patient-derived xenograft and stem-like glioblastoma cells.  Transcriptome based GSEA analysis suggests that metabolic reprogramming is involved with synergistic reduction of oxidative and glycolytic pathways in the combination treatment. Extracellular flux analysis confirms that combined HDAC inhibition and BRD inhibition blunts oxidative and glycolytic metabolism of cancer cells, leading to a depletion of intracellular ATP production and total ATP levels. In turn, energy deprivation drives an integrated stress response, originating from the endoplasmic reticulum. This results in an increase in pro-apoptotic Noxa. Aside from Noxa, we encounter a compensatory increase of anti-apoptotic Mcl-1 protein. Pharmacological, utilizing the FDA-approved drug sorafenib, and genetic inhibition of Mcl-1 enhanced the effects of the combination therapy. Finally, we show in orthotopic patient-derived xenografts of GBM, that the combination treatment reduces tumor growth, and that the triple therapy, involving clinically validated compounds, panobinostat, OTX015 and sorafenib further enhances these effects, culminating in a significant regression of tumors in vivo. Conclusion: Overall, these results warrant clinical testing of this novel, efficacious combination therapy.

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