Clump, D. A. | Search bioRxiv

bioRxiv2026

Transient ATR inhibition following ionizing radiation enhances immune-mediated antitumor response and survival

BackgroundATR activation following DNA damage from cancer treatments such as radiation can mitigate anticancer efficacy, making ATR inhibitors (ATRi) an attractive therapeutic. In vivo and in vitro studies have shown enhanced tumor cell radiosensitivity with the ATRi ceralasertib, elimusertib, and berzosertib, however, the potentiating effect of ATRi on ionizing radiation (IR) through immune-based mechanisms has only been studied with ceralasertib. MethodsWe aimed to determine if antitumor immune responses observed with ceralasertib in combination with IR extend to the other ATRi class members in the preclinical CT26 mouse model. We also examined the relationship between exposure and immune stimulation, efficacy and survival outcomes of each ATRi when combined with IR. ResultsCeralasertib and elimusertib, not berzosertib, synergized with IR in a dose and schedule-dependent manner to modify tumor antigen-specific CD8+ T cell populations in the draining lymph node. Transient ATRi therapy, combined with IR, enhances antitumor efficacy, promoted tumor shrinkage, and increased survival. ATRi elicited differential inflammatory gene induction and dose-dependent unique cytotoxicity profiles in vitro. ConclusionThe immune mediated antitumor effect of ATRi combined with radiation is dose and schedule dependent, and while likely a class effect, may differ between ATRi compounds.

cancer biology↗

bioRxiv2022

Short-course but not prolonged treatment with ATR inhibitor AZD6738 integrates with radiotherapy to generate a tumor antigen-specific CD8+ T cell expansion in the periphery

ATR kinase is a central regulator of the DNA damage response. While ATR kinase inhibitors (ATRis) are known to sensitize cancer cells to DNA damage, their effect on immune cells is not known. Here we show in mice that short-course AZD6738 (ATRi) on days 1-3 decreases proliferating T cells in the tumor and periphery and that cessation of ATRi causes a proliferative rebound. Integrating radiation on days 1-2 (RT) with ATRi on days 1-3 increases IFN-{beta} in the tumor and activates tumor antigen-specific CD8+ T cells in the tumor-draining lymph node (DLN). RT with short-course ATRi induces an expansion of tumor antigen-specific CD8+ T cells in the DLN. In contrast, RT with prolonged daily ATRi blocks expansion of antigen-specific CD8+ T cells, despite increased IFN-{beta} and activation of CD8+ T cells. Our data identifies critical schedule considerations for ATRi with RT, immunotherapy and genotoxic therapies.

cancer biology↗