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 XiongMeredith A. Morgan, Alnawaz Rehemtualla, Maria G. Castro, Pedro Lowenstein, Sriram Chandrasekaran, Theodore S. Lawrence, Costas A. Lyssiotis, Daniel R. Wahl

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number3811
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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  • Cite this

    Zhou, W., Yao, Y., Scott, A. J., Wilder-Romans, K., Dresser, J. J., Werner, C. K., Sun, H., Pratt, D., Sajjakulnukit, P., Zhao, S. G., Davis, M., Nelson, B. S., Halbrook, C. J., Zhang, L., Gatto, F., Umemura, Y., Walker, A. K., Kachman, M., Sarkaria, J. N., ... Wahl, D. R. (2020). Purine metabolism regulates DNA repair and therapy resistance in glioblastoma. Nature communications, 11(1), [3811]. https://doi.org/10.1038/s41467-020-17512-x