Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 131, Issue 1, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI142158
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Funding
- National Cancer Institute [F30 CA206424, R35 CA197616]
- Pediatric Brain Tumor Foundation
- Hannah's Heroes St. Baldrick's Research Grant
- Leon Levine Foundation
- National Cancer Institute (Duke Brain) [SPORE P50-CA19099]
- Fly A Kite Foundation
- Cristian Rivera Foundation
- Rory David Deutsch Foundation
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The study suggests that deleting Atm in DIPG models can enhance tumor radiosensitivity, especially in the absence of p53. Mice with p53 wild-type tumors also showed improved survival after radiotherapy, regardless of Atm deletion. Tumor genotype may determine whether inhibiting ATM during radiotherapy is an effective approach.
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 p5.3 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 Nqca 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.
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