Purine metabolism regulates DNA repair and therapy resistance in glioblastoma
Journal article, 2020
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.
Author
Weihua Zhou
University of Michigan
Yangyang Yao
University of Michigan
Nanchang University
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, Biology and Biological Engineering, Systems and Synthetic Biology
Yoshie Umemura
University of Michigan
Angela K. Walker
University of Michigan
Maureen Kachman
University of Michigan
Jann N. Sarkaria
Mayo Clinic
Jianping Xiong
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
2041-1723 (ISSN) 20411723 (eISSN)
Vol. 11 1 3811Subject Categories
Pharmaceutical Sciences
Pharmacology and Toxicology
Hematology
DOI
10.1038/s41467-020-17512-x