Targeting NAD + Biosynthesis Overcomes Panobinostat and Bortezomib-Induced Malignant Glioma Resistance.

Autor:	Jane EP; Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania.; University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Premkumar DR; Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania. daniel.premkumar@chp.edu ian.pollack@chp.edu.; University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; University of Pittsburgh Cancer Institute Brain Tumor Center, Pittsburgh, Pennsylvania., Thambireddy S; Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania., Golbourn B; Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania., Agnihotri S; Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania.; University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; University of Pittsburgh Cancer Institute Brain Tumor Center, Pittsburgh, Pennsylvania., Bertrand KC; Texas Children's Hospital, Baylor College of Medicine, Houston, Texas., Mack SC; Texas Children's Hospital, Baylor College of Medicine, Houston, Texas., Myers MI; Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania., Chattopadhyay A; Molecular Biology Information Service, University of Pittsburgh, Pittsburgh, Pennsylvania., Taylor DL; Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Schurdak ME; Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Stern AM; Drug Discovery Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Pollack IF; Department of Neurosurgery, University of Pittsburgh, Pittsburgh, Pennsylvania. daniel.premkumar@chp.edu ian.pollack@chp.edu.; University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; University of Pittsburgh Cancer Institute Brain Tumor Center, Pittsburgh, Pennsylvania.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2020 Jul; Vol. 18 (7), pp. 1004-1017. Date of Electronic Publication: 2020 Apr 01.
DOI:	10.1158/1541-7786.MCR-19-0669
Abstrakt:	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-naïve 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. 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. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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