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Purine metabolism r...
Purine metabolism regulates DNA repair and therapy resistance in glioblastoma
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- Zhou, Weihua (author)
- University of Michigan
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- Yao, Yangyang (author)
- University of Michigan,Nanchang University
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- Scott, Andrew J. (author)
- University of Michigan
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- Wilder-Romans, Kari (author)
- University of Michigan
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- Dresser, Joseph J. (author)
- University of Michigan
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- Werner, Christian K. (author)
- University of Michigan
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- Sun, Hanshi (author)
- University of Michigan
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- Pratt, Drew (author)
- University of Michigan
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- Sajjakulnukit, Peter (author)
- University of Michigan
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- Zhao, Shuang G. (author)
- University of Michigan
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- Davis, Mary (author)
- University of Michigan
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- Nelson, Barbara S. (author)
- University of Michigan
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- Halbrook, Christopher J. (author)
- University of Michigan
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- Zhang, Li (author)
- University of Michigan
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- Gatto, Francesco, 1987 (author)
- Chalmers tekniska högskola,Chalmers University of Technology
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- Umemura, Yoshie (author)
- University of Michigan
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- Walker, Angela K. (author)
- University of Michigan
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- Kachman, Maureen (author)
- University of Michigan
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- Sarkaria, Jann N. (author)
- Mayo Clinic
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- Xiong, Jianping (author)
- Nanchang University
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- Morgan, Meredith A. (author)
- University of Michigan
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- Rehemtualla, Alnawaz (author)
- University of Michigan
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- Castro, Maria G. (author)
- University of Michigan
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- Lowenstein, Pedro (author)
- University of Michigan
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- Chandrasekaran, Sriram (author)
- University of Michigan
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- Lawrence, Theodore S. (author)
- University of Michigan
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- Lyssiotis, Costas A. (author)
- University of Michigan
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- Wahl, Daniel R. (author)
- University of Michigan
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(creator_code:org_t)
- 2020-07-30
- 2020
- English.
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 11:1
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Abstract
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- Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance. Treatments that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we find that purine metabolites, especially guanylates, strongly correlate with radiation resistance. Inhibiting GTP synthesis radiosensitizes GBM cells and patient-derived neurospheres by impairing DNA repair. Likewise, administration of exogenous purine nucleosides protects sensitive GBM models from radiation by promoting DNA repair. Neither modulating pyrimidine metabolism nor purine salvage has similar effects. An FDA-approved inhibitor of GTP synthesis potentiates the effects of radiation in flank and orthotopic patient-derived xenograft models of GBM. High expression of the rate-limiting enzyme of de novo GTP synthesis is associated with shorter survival in GBM patients. These findings indicate that inhibiting purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
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- By the author/editor
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Zhou, Weihua
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Yao, Yangyang
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Scott, Andrew J.
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Wilder-Romans, K ...
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Dresser, Joseph ...
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Werner, Christia ...
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show more...
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Sun, Hanshi
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Pratt, Drew
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Sajjakulnukit, P ...
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Zhao, Shuang G.
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Davis, Mary
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Nelson, Barbara ...
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Halbrook, Christ ...
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Zhang, Li
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Gatto, Francesco ...
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Umemura, Yoshie
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Walker, Angela K ...
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Kachman, Maureen
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Sarkaria, Jann N ...
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Xiong, Jianping
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Morgan, Meredith ...
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Rehemtualla, Aln ...
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Castro, Maria G.
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Lowenstein, Pedr ...
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Chandrasekaran, ...
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Lawrence, Theodo ...
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Lyssiotis, Costa ...
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Wahl, Daniel R.
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmaceutical S ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmacology and ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
- Articles in the publication
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Nature Communica ...
- By the university
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Chalmers University of Technology