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Purine metabolism r...
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Zhou, WeihuaUniversity of Michigan
(author)
Purine metabolism regulates DNA repair and therapy resistance in glioblastoma
- Article/chapterEnglish2020
Publisher, publication year, extent ...
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2020-07-30
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Springer Science and Business Media LLC,2020
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electronicrdacarrier
Numbers
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LIBRIS-ID:oai:research.chalmers.se:f2a160fd-15df-4ceb-a9ae-32f6c5eddd15
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https://doi.org/10.1038/s41467-020-17512-xDOI
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https://research.chalmers.se/publication/518406URI
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Language:English
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Summary in:English
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Subject category:art swepub-publicationtype
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Subject category:ref swepub-contenttype
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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.
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Yao, YangyangUniversity of Michigan,Nanchang University
(author)
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Scott, Andrew J.University of Michigan
(author)
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Wilder-Romans, KariUniversity of Michigan
(author)
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Dresser, Joseph J.University of Michigan
(author)
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Werner, Christian K.University of Michigan
(author)
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Sun, HanshiUniversity of Michigan
(author)
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Pratt, DrewUniversity of Michigan
(author)
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Sajjakulnukit, PeterUniversity of Michigan
(author)
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Zhao, Shuang G.University of Michigan
(author)
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Davis, MaryUniversity of Michigan
(author)
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Nelson, Barbara S.University of Michigan
(author)
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Halbrook, Christopher J.University of Michigan
(author)
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Zhang, LiUniversity of Michigan
(author)
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Gatto, Francesco,1987Chalmers tekniska högskola,Chalmers University of Technology(Swepub:cth)gatto
(author)
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Umemura, YoshieUniversity of Michigan
(author)
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Walker, Angela K.University of Michigan
(author)
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Kachman, MaureenUniversity of Michigan
(author)
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Sarkaria, Jann N.Mayo Clinic
(author)
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Xiong, JianpingNanchang University
(author)
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Morgan, Meredith A.University of Michigan
(author)
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Rehemtualla, AlnawazUniversity of Michigan
(author)
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Castro, Maria G.University of Michigan
(author)
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Lowenstein, PedroUniversity of Michigan
(author)
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Chandrasekaran, SriramUniversity of Michigan
(author)
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Lawrence, Theodore S.University of Michigan
(author)
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Lyssiotis, Costas A.University of Michigan
(author)
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Wahl, Daniel R.University of Michigan
(author)
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University of MichiganNanchang University
(creator_code:org_t)
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In:Nature Communications: Springer Science and Business Media LLC11:12041-17232041-1723
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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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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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