Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

• DOI: 10.1038/s41467-020-17512-x
• Publication Date: 2020-07-30T10:24:08Z
• Authors: 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. Ha...; 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 Chandrasek...; Theodore S. Lawrence; Costas A. Lyssiotis; Daniel R. Wahl
• Keywords: Purine metabolism; Nucleotide salvage

Abstract Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance. Treatments that are effective independent of genotype urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens genomically-distinct models GBM, we find purine metabolites, especially guanylates, strongly correlate Inhibiting GTP synthesis radiosensitizes GBM cells and patient-derived neurospheres by impairing DNA repair. Likewise, administration exogenous nucleosides protects sensitive from promoting Neither modulating pyrimidine metabolism nor salvage has similar effects. An FDA-approved inhibitor potentiates the effects flank orthotopic xenograft GBM. High expression rate-limiting enzyme de novo associated shorter survival patients. These findings indicate inhibiting may be promising strategy overcome this genomically heterogeneous disease.