Abstract 2829: Acetyl-CoA Acetyltransferase 2 confers radioresistance by inhibiting ferroptosis and enhancing the phosphorylation of AKT-S473 in esophageal squamous cell carcinoma

Abstract Purpose: The overall efficacy of patients with esophageal squamous cell carcinoma (ESCC) is not high due to the lack of markers to evaluate concurrent chemoradiotherapy (CCRT) resistance, which is dominated by radiotherapy. The aim of this study is to identify a radioresistant protein from proteomics and explore its molecular mechanism. Methods and Materials: The proteomic data of pre-treatment biopsy tissues of 18 ESCC patients with CCRT (complete response CR group, n = 8; incomplete response <CR group, n = 10) was collected, combined with PXD021701 to explore the radioresistant candidate. Subsequently, immunohistochemistry of 126 paraffin embedded biopsies was used for validation. The ESCC cell models with overexpression, knockdown or knockout of Acetyl-CoA Acetyltransferase 2 (ACAT2) were applied for exploring its effects on radioresistance using clonogenic assay underwent ionizing radiation (IR). ROS, C11-BODIPY, Fer-1 (ferrostatin inhibitor) and western blotting analysis were employed to reveal the potential mechanism ACAT2 triggered after IR. Results: Enrichment analysis of differentially expressed proteins (<CR vs. CR) showed that the pathways of CCRT resistance molecules in ESCC were related to lipid metabolism, while the sensitive ones were mainly aggregated to immunity pathways. ACAT2 was selected from proteomics and verified as a risk factor of overall survival and a radioresistant factor among ESCC patients with CCRT or radiotherapy by immunohistochemistry. ACAT2 overexpression conferred ESCC cell resistance to IR treatment, whereas the ACAT2 knockdown or knockout ones were sensitive to IR. ACAT2 knockout cells were prone to produce ROS and enhance lipid peroxidation after IR, which was rescued by Fer-1. ACAT2 knockout also inhibited GPX4 and phosphorylation of AKT-S473 site after IR. Conclusion: ACAT2 is negatively associated with the response of radiotherapy and prognosis of ESCC patients, suggesting ACAT2 as an effective therapy target to enhance radiosensitivity of ESCC. This work was supported by the National Natural Science Foundation of China (82273108 and 82173034), the Innovative Team Grant of Guangdong Department of Education (2021KCXTD005), the Science and Technology Special Fund project of Guangdong Province in 2021 (No. 210729156901797) and the 2020 Li Ka Shing Foundation Cross-Disciplinary Research Grant (2020LKSFG07B) Citation Format: Heng Jinghua, Li Enmin, Xu Liyan. Acetyl-CoA Acetyltransferase 2 confers radioresistance by inhibiting ferroptosis and enhancing the phosphorylation of AKT-S473 in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2829.