Radiation and ATM inhibition: the heart of the matter

Abstract

Numerous in vitro studies have shown that human cell lines lacking functional ATM are extremely radiosensitive. In this issue, Moding et al. demonstrate using a murine model of sarcoma that deletion of the Atm gene has much less of a radiosensitizing effect on normal cardiac endothelia than on rapidly proliferating tumor endothelia. This work confounds our assumptions about the generality of the role of ATM in radiation sensitivity and the potential use of ATM inhibitors as radiosensitizers.

Figure 1. Generation of genetically engineered mice with sarcoma driven by deletion of p53 and expression of mutant Kras in mice with endothelial cell–specific ATM loss.

(A) Moding et al. developed this model (14) using genetically engineered mice in which Atm was selectively deleted in the vast majority of endothelial cells due to transgenic expression of the recombinase Cre from the endothelial-selective VE-cadherin promoter. (B) Subsequently, a sarcoma was induced in these mice. In addition to the alterations of the Atm gene, these mice had p53 flanked by Frt sequences that can be cleaved and deleted by a different recombinase, FlpO. The mice further contained a mutant Kras that is inhibited in its expression by stop sequences that also can be cleaved and deleted by FlpO. Injection of an adenovirus expressing FlpO resulted in expression of oncogenic Kras and loss of p53 and led to sarcoma formation at the site of the injection. Notably, the tumor itself expressed wild-type ATM. (C) Finally, both the tumor and the heart were irradiated, allowing for comparison of tumor endothelial and cardiac endothelial response to radiation.