Comparative in vivo toxicology of ATR inhibitors ceralasertib, elimusertib, and berzosertib alone and in combination with ionizing radiation

Abstract

Ionizing radiation (IR) induces damage in the form of DNA strand breaks. As an apical initiator of the DNA damage response, Ataxia telangiectasia and Rad3-related (ATR) mitigates DNA damage, limiting therapeutic efficacy. Small molecule ATR inhibitors (ATRi) restrict this effect and sensitize cancer cells to radiation-induced damage. However, the impact of ATR inhibition in non-malignant tissues following IR is currently unknown. Here, we document the impact of ATRi on murine toxicity profiles following total body irradiation (TBI). Mice were stratified to receive single-dose ATRi (ceralasertib, elimusertib, or berzosertib), 6 Gy TBI, or the combination. Mice were euthanized 48 h post TBI. Blood and tissues were collected for analysis of complete blood counts and histopathology. To further distinguish toxicity profiles, IC₅₀ values were compared between ATRi. Pharmacokinetics (PK) and pharmacodynamics (PD) were considered as potential explanatory factors of differences in toxicity profiles. Elimusertib was determined to be the most potent ATRi, and ceralasertib the least. We observed neutrophilia with all ATRi. We found that ATRi did not exacerbate any TBI-induced toxicities in mice. Berzosertib presented a unique profile among all ATRi across several toxicity endpoints, including modest amelioration of TBI-associated effects on spleen and lymphocyte and white blood cell counts. Cardiotoxicity was observed following single-dose ceralasertib, but no other ATRi, possibly due to high unbound plasma drug concentrations. Our results further support and guide clinical development of ATRi in clinic.

Keywords: ATR Inhibitor; Berzosertib; Ceralasertib; Elimusertib; Pathology; Radiation; Toxicity.