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.
Original language | English (US) |
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Article number | e142158 |
Journal | Journal of Clinical Investigation |
Volume | 131 |
Issue number | 1 |
DOIs | |
State | Published - Jan 4 2021 |
Funding
This work is dedicated to the memory of Rose Sugarman, who died from a DIPG. We thank John Nouls from the Duke Center for In Vivo Microscopy for assistance in obtaining the MRI. This work was supported by grants to DGK from the National Cancer Institute (R35 CA197616), Pediatric Brain Tumor Foundation, Hannah’s Heroes St. Baldrick’s Research Grant, and The Leon Levine Foundation. DGK and KD were supported by the National Cancer Institute (Duke Brain SPORE P50-CA19099). MC was supported by the National Cancer Institute (F30 CA206424). OJB was supported by Maddox’s Warriors, the Fly A Kite Foundation, Cristian Rivera Foundation, and the Rory David Deutsch Foundation.
ASJC Scopus subject areas
- General Medicine