Targeting NAD+ Biosynthesis Overcomes Panobinostat and Bortezomib-Induced Malignant Glioma Resistance
- 1 July 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Research
- Vol. 18 (7), 1004-1017
- https://doi.org/10.1158/1541-7786.MCR-19-0669
Abstract
To improve therapeutic responses in patients with glioma, new combination therapies that exploit a mechanistic understanding of the inevitable emergence of drug resistance are needed. Intratumoral heterogeneity enables a low barrier to resistance in individual patients with glioma. 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 histone deacetylase 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 pharmacologic screening of resistant versus drug-naive cells. Quinolinic acid phosphoribosyltransferase (QPRT), the rate-determining enzyme for de novo synthesis of 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. Pharmacologic 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.Other Versions
Funding Information
- Translational Brain Tumor Research Fund
- Children's Hospital of Pittsburgh Foundation
- University of Pittsburgh Cancer Institute (P30CA047904)
- NIH NCI
- UPCI
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