The Effect of Atm Loss on Radiosensitivity of a Primary Mouse Model of Pten-Deleted Brainstem Glioma

Abstract

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.

Ataxia-telangiectasia mutated(Atm) disruption sensitizes spatially-directed H3.3K27M/TP53 diffuse midline gliomas to radiation therapy

“…A recent study identified ATM inhibition as a potent radiosensitization strategy in a variety of patient-derived pediatric high-grade glioma models 6 . We found that functional ATM loss radiosensitized primary mouse models of DMG driven by p53 loss, but not those that were p53 wildtype 5,11 . ATM loss increased tumor sensitivity to radiotherapy by radiosensitization of neoplastic cells rather than vasculature 12 .…”

“…Almost all p53-altered primary mouse models are radioresistant and are radiosensitized by Atm loss, including (i) a model driven by p53 loss with wild type H3f3a 5 , (ii) a model driven by both p53 loss and by loss of Ink4A/ARF 5 , and (iii) the H3.3K27M/TP53 mutant model reported here (Figure 2C). In contrast, Atm loss is unable to radiosensitize primary p53-wildtype brainstem glioma mouse models, including models driven by Ink4A/ARF loss 5 and models driven by Pten loss 11 . Of note, a recent study comprehensively profiled that pharmacologic ATM inhibition radiosensitized both p53-mutant and p53-wild type patient-derived models of DMG and pediatric high-grade glioma 6 .…”

“…Here, we examine strategies to exploit the genomically-stressed cell state in H3.3K27M/TP53-altered DMG. We improve upon previous models that delivered H3.3K27M from an exogenous RCAS payload 13 11 by combining the RCAS/tv-a system with H3f3a LSL-K27M-Tag mice to express H3.3K27M from the endogenous H3f3a locus. This autochthonous mouse model enabled us to analyze the impact of Atm loss in the context of H3.3K27M/TP53-altered brain tumors to mimic human DMG 10 .…”

“…To date, conditional H3.3K27M alleles have not been interrogated in an entirely spatially controlled manner. We and others have used the RCAS/tv-a retroviral system for spatially-directed modulation of glioma tumorigenesis in the mouse 5,[11][12][13][14][15] . The RCAS/tv-a platform has been used to deliver exogenous H3.3K27M 13,14,16 , but to our knowledge it has not been used to edit the endogenous H3f3a allele.…”

Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization

“…The analysis of only 10 glioma models limits our ability to comprehensively evaluate how the spectrum of genetic alterations influence treatment outcome. For example, PTEN deletion is common in GBM and was reported to limit the radiosensitizing effects of ATM deletion in a model of brainstem glioma ( 64 ). Likewise, the interplay between inherent radiation sensitivity and radiosensitizing effects of ATM inhibition needs to be explored.…”