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Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models
Katherine Deland, … , Oren J. Becher, David G. Kirsch
Katherine Deland, … , Oren J. Becher, David G. Kirsch
Published September 29, 2020
Citation Information: J Clin Invest. 2021;131(1):e142158. https://doi.org/10.1172/JCI142158.
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Research Article Oncology Article has an altmetric score of 6

Tumor genotype dictates radiosensitization after Atm deletion in primary brainstem glioma models

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Abstract

Diffuse intrinsic pontine glioma (DIPG) kills more children than any other type of brain tumor. Despite clinical trials testing many chemotherapeutic agents, palliative radiotherapy remains the standard treatment. Here, we utilized Cre/loxP technology to show that deleting Ataxia telangiectasia mutated (Atm) in primary mouse models of DIPG can enhance tumor radiosensitivity. Genetic deletion of Atm improved survival of mice with p53-deficient but not p53 wild-type gliomas after radiotherapy. Similar to patients with DIPG, mice with p53 wild-type tumors had improved survival after radiotherapy independent of Atm deletion. Primary p53 wild-type tumor cell lines induced proapoptotic genes after radiation and repressed the NRF2 target, NAD(P)H quinone dehydrogenase 1 (Nqo1). Tumors lacking p53 and Ink4a/Arf expressed the highest level of Nqo1 and were most resistant to radiation, but deletion of Atm enhanced the radiation response. These results suggest that tumor genotype may determine whether inhibition of ATM during radiotherapy will be an effective clinical approach to treat DIPGs.

Authors

Katherine Deland, Bryce F. Starr, Joshua S. Mercer, Jovita Byemerwa, Donna M. Crabtree, Nerissa T. Williams, Lixia Luo, Yan Ma, Mark Chen, Oren J. Becher, David G. Kirsch

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Figure 2

Deletion of Atm in p53-deficient gliomas improves tumor response to radiation.

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Deletion of Atm in p53-deficient gliomas improves tumor response to radi...
(A) Percentage recombination of the floxed allele of Atm in flow-sorted glioma cells as assessed by droplet digital PCR. (B) Time to tumor development after injection in nPAfl/+ and nPAfl/fl mice as detected through in vivo bioluminescence imaging. Each circle represents 1 mouse. (C) Kaplan-Meier plot of overall survival in tumor-bearing mice after tumor detection. Quantification of the fractional area of positive staining for (D) pATM 2 hours after 10 Gy or (E) pKAP1 1 hour after 10 Gy in primary gliomas. (F) Number of TUNEL+ cells in nPAfl/+ and nPAfl/fl tumors 24 hours after 10 Gy whole-brain irradiation. *P < 0.05 by t test (2 tailed). (G) Clonogenic survival assay using stroma-depleted nPAfl/+ and nPAfl/fl tumor cell lines (n = 2 cell lines per genotype). *P < 0.05 by 2-way ANOVA followed by Bonferroni’s multiple-comparison test. (H) Kaplan-Meier plot of overall survival in tumor-bearing mice after 3 daily fractions of 10 Gy radiation therapy delivered to the whole brain. *P < 0.05 by log rank test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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