Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

Authors

• Weihua Zhou, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA.
• Yangyang Yao, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA.
• Andrew J. Scott, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA.
• Kari Wilder-Romans, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA.
• Joseph J. Dresser, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA.
• Christian K. Werner, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA.
• Hanshi Sun, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA.
• Drew Pratt, Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
• Peter Sajjakulnukit, Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
• Shuang G. Zhao, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA.
• Mary Davis, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA.
• Barbara S. Nelson, Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
• Christopher J. Halbrook, Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
• Li Zhang, Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
• Francesco Gatto, Department of Biology and Biological Engineering, Chalmers University of Technology, 41296, Göteborg, Sweden.
• Yoshie Umemura, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA.
• Angela K. Walker, Biomedical Research Core Facilities, University of Michigan, Ann Arbor, MI, 48109, USA.
• Maureen Kachman, Biomedical Research Core Facilities, University of Michigan, Ann Arbor, MI, 48109, USA.
• Jann N. Sarkaria, Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 55902, USA.
• Jianping Xiong, Department of Oncology, the First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, PR China.
• Meredith A. Morgan, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA.
• Alnawaz Rehemtualla, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA.
• Maria G. Castro, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA.
• Pedro Lowenstein, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA.
• Sriram Chandrasekaran, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA.
• Theodore S. Lawrence, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA.
• Costas A. Lyssiotis, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA.
• Daniel R. Wahl, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA. dwahl@med.umich.edu.

Document Type

Article

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.

Medical Subject Headings

Animals; Brain Neoplasms (genetics, radiotherapy); Cell Line, Tumor; DNA Repair (genetics); Female; Glioblastoma (genetics, radiotherapy); Guanosine Monophosphate (metabolism); Humans; Male; Mice; Mice, Knockout; Mice, SCID; Purine Nucleosides (metabolism); Radiation Tolerance (genetics); Xenograft Model Antitumor Assays

Publication Date

7-30-2020

Publication Title

Nature communications

E-ISSN

2041-1723

Volume

11

Issue

1

First Page

3811

PubMed ID

32732914

Digital Object Identifier (DOI)

10.1038/s41467-020-17512-x

Recommended Citation

Zhou, Weihua; Yao, Yangyang; Scott, Andrew J.; Wilder-Romans, Kari; Dresser, Joseph J.; Werner, Christian K.; Sun, Hanshi; Pratt, Drew; Sajjakulnukit, Peter; Zhao, Shuang G.; Davis, Mary; Nelson, Barbara S.; Halbrook, Christopher J.; Zhang, Li; Gatto, Francesco; Umemura, Yoshie; Walker, Angela K.; Kachman, Maureen; Sarkaria, Jann N.; Xiong, Jianping; Morgan, Meredith A.; Rehemtualla, Alnawaz; Castro, Maria G.; Lowenstein, Pedro; Chandrasekaran, Sriram; Lawrence, Theodore S.; Lyssiotis, Costas A.; and Wahl, Daniel R., "Purine metabolism regulates DNA repair and therapy resistance in glioblastoma" (2020). Neurology. 1456.
https://scholar.barrowneuro.org/neurology/1456