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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Deland, K; Starr, BF; Mercer, JS; Byemerwa, J; Crabtree, DM; Williams, NT; Luo, L; Ma, Y; Chen, M; Becher, OJ; Kirsch, DG

Published Date

  • January 4, 2021

Published In

Volume / Issue

  • 131 / 1

PubMed ID

  • 32990677

Pubmed Central ID

  • PMC7773366

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI142158

Language

  • eng

Conference Location

  • United States