TY - JOUR
T1 - Purine metabolism regulates DNA repair and therapy resistance in glioblastoma
AU - Zhou, Weihua
AU - Yao, Yangyang
AU - Scott, Andrew J.
AU - Wilder-Romans, Kari
AU - Dresser, Joseph J.
AU - Werner, Christian K.
AU - Sun, Hanshi
AU - Pratt, Drew
AU - Sajjakulnukit, Peter
AU - Zhao, Shuang G.
AU - Davis, Mary
AU - Nelson, Barbara S.
AU - Halbrook, Christopher J.
AU - Zhang, Li
AU - Gatto, Francesco
AU - Umemura, Yoshie
AU - Walker, Angela K.
AU - Kachman, Maureen
AU - Sarkaria, Jann N.
AU - Xiong, Jianping
AU - Morgan, Meredith A.
AU - Rehemtualla, Alnawaz
AU - Castro, Maria G.
AU - Lowenstein, Pedro
AU - Chandrasekaran, Sriram
AU - Lawrence, Theodore S.
AU - Lyssiotis, Costas A.
AU - Wahl, Daniel R.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-17512-x
DO - 10.1038/s41467-020-17512-x
M3 - Article
C2 - 32732914
AN - SCOPUS:85088835787
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3811
ER -