Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

Weihua Zhou, Yangyang Yao, Andrew J. Scott, Kari Wilder-Romans, Joseph J. Dresser, Christian K. Werner, Hanshi Sun, Drew Pratt, Peter Sajjakulnukit, Shuang G. Zhao, Mary Davis, Barbara S. Nelson, Christopher J. Halbrook, Li Zhang, Francesco Gatto, Yoshie Umemura, Angela K. Walker, Maureen Kachman, Jann N. Sarkaria, Jianping Xiong, Meredith A. Morgan, Alnawaz Rehemtualla, Maria G. Castro, Pedro Lowenstein, Sriram Chandrasekaran, Theodore S. Lawrence, Costas A. Lyssiotis and Daniel R. Wahl ()
Additional contact information
Weihua Zhou: University of Michigan
Yangyang Yao: University of Michigan
Andrew J. Scott: University of Michigan
Kari Wilder-Romans: University of Michigan
Joseph J. Dresser: University of Michigan
Christian K. Werner: University of Michigan
Hanshi Sun: University of Michigan
Drew Pratt: University of Michigan
Peter Sajjakulnukit: University of Michigan
Shuang G. Zhao: University of Michigan
Mary Davis: University of Michigan
Barbara S. Nelson: University of Michigan
Christopher J. Halbrook: University of Michigan
Li Zhang: University of Michigan
Francesco Gatto: Chalmers University of Technology
Yoshie Umemura: University of Michigan
Angela K. Walker: University of Michigan
Maureen Kachman: University of Michigan
Jann N. Sarkaria: Mayo Clinic
Jianping Xiong: the First Affiliated Hospital of Nanchang University
Meredith A. Morgan: University of Michigan
Alnawaz Rehemtualla: University of Michigan
Maria G. Castro: University of Michigan
Pedro Lowenstein: University of Michigan
Sriram Chandrasekaran: University of Michigan
Theodore S. Lawrence: University of Michigan
Costas A. Lyssiotis: University of Michigan
Daniel R. Wahl: University of Michigan

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-17512-x

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