Atm loss does not radiosensitize a primary mouse model of Pten-deleted brainstem glioma

Diffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase ataxia telangiectasia mutated (ATM), which orchestrates the cellular response to radiation-induced DNA damage, may enhance the efficacy of radiation therapy. Diffuse midline gliomas in the brainstem contain loss-of-function mutations in the tumor suppressor PTEN , or functionally similar alterations in the phosphoinositide-3-kinase (PI3K) pathway, at moderate frequency. Here, we sought to determine if Atm inactivation could radiosensitize a primary mouse model of brainstem glioma driven by Pten loss. Using Cre/loxP recombinase technology and the RCAS/TVA retroviral gene delivery system, we established a mouse model of brainstem glioma driven by Pten deletion. We find that Pten -null brainstem gliomas are relatively radiosensitive at baseline. In addition, we show that deletion of Atm in the tumor cells does not extend survival of mice bearing Pten -null brainstem gliomas after focal brain irradiation. These results characterize a novel primary mouse model of PTEN -mutated brainstem glioma and provide insights into the mechanism of radiosensitization by Atm deletion, which may guide the design of future clinical trials. Brief Summary We develop a mouse model of PTEN -mutated brainstem glioma and find that perturbation of the ATM does not enhance radiation efficacy in this model. ### Competing Interest Statement DGK owns stock and is on the scientific advisory board of Lumicell, which is commercializing intraoperative imaging technology. DGK is a co-founder of Xrad Therapeutics, which is developing radiosensitizers. The DGK laboratory receives research funding from Merck, Bristol Myers Squibb, Xrad Therapeutics, and Varian Medical Systems, but this funding did not support the work in this manuscript. ZJR owns intellectual property related to genetic testing for brain tumors that is managed by Duke Office of Licensing and Ventures and has been licensed to Genetron Health.