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Targeting NAD+ biosynthesis overcomes panobinostat and bortezomib-induced malignant glioma resistance

To improve therapeutic responses in glioma patients, new combination therapies that exploit a mechanistic understanding of the inevitable emergence of drug resistance are needed. Intra-tumoral heterogeneity enables a low barrier to resistance in individual glioma patients. We reasoned that targeting two or more fundamental processes that gliomas are particularly dependent upon could result in pleiotropic effects that would reduce the diversity of resistant subpopulations allowing convergence to a more robust therapeutic strategy. In contrast to the cytostatic responses observed with each drug alone, the combination of the HDAC inhibitor panobinostat and the proteasome inhibitor bortezomib synergistically induced apoptosis of adult and pediatric glioma cell lines at clinically achievable doses. Resistance that developed was examined using RNA sequencing and pharmacological screening of resistant versus drug naïve cells. Quinolinic acid phosphoribosyltransferase (QPRT), the rate-determining enzyme for de novo synthesis of nicotinamide adenine dinucleotide (NAD+) from tryptophan, exhibited particularly high differential gene expression in resistant U87 cells and protein expression in all resistant lines tested. Reducing QPRT expression reversed resistance, suggesting that QPRT is a selective and targetable dependency for the panobinostat-bortezomib resistance phenotype. Pharmacological inhibition of either NAD+ biosynthesis or processes such as DNA repair that consume NAD+ or their simultaneous inhibition with drug combinations, specifically enhanced apoptosis in treatment-resistant cells. Concomitantly, de novo vulnerabilities to known drugs were observed. Implications: These data provide new insights into mechanisms of treatment resistance in gliomas, hold promise for targeting recurrent disease, and provide a potential strategy for further exploration of next generation inhibitors.

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S1030 Panobinostat (LBH589) Panobinostat (LBH589, NVP-LBH589) is a novel broad-spectrum HDAC inhibitor with IC50 of 5 nM in a cell-free assay. Panobinostat (LBH589) induces autophagy and apoptosis. Panobinostat effectively disrupts HIV latency in vivo. Phase 3.

Related Targets

HDAC