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 3811

Subject Categories

Pharmaceutical Sciences

Pharmacology and Toxicology

Hematology

DOI

10.1038/s41467-020-17512-x

More information

Latest update

9/1/2020 8