Abstract 6428: Targeting SMARCAL1 as a therapeutic strategy to enhance cGAS/STING signaling in gastric cancer

Abstract

Abstract Gastric cancer is one of the leading causes of cancer death in Eastern Asia. Although immunotherapy, such as immune checkpoint blockade, is an emerging therapeutic strategy against gastric cancer, only a fraction of cancer patients show a therapeutic response. Therefore, developing a novel therapeutic strategy to turn a “cold” tumor into a “hot” tumor is considered a crucial issue in cancer treatment. By methylomic analysis, we found that SMARCAL1 is one of the STAT3 targets which might be regulated by STAT3-mediated promoter methylation. Moreover, an inverse correlation between SMARCAL1 promoter methylation and expression was observed in the TCGA online database and in our cell lines experiment. Bisulfite pyrosequencing also showed a significant hypomethylation of SMARCAL1 compared to gastritis and adjacent normal in our in-house cohort (gastritis n=15; IM n=13; cancer n=58). More importantly, SMARCAL1 knockdown showed increased sensitivity of gastric cancer cell lines to DNA-damaging agents and increase the expression of cGAS and its downstream target, IFNB1. Therefore, in this study, we propose SMARCAL1 as a therapeutic target for improving the efficiency of immunotherapy by enhancing the cGAS/STING signaling pathway. Citation Format: Po-Yen Hsu, Yu-Ming Chuang, Shu-Hui LIN, Yu-Ting Lee, Yin-Chen Chen, Enders K.W. Ng, Kun-Tu YEH, Alfred S.L. Cheng, Michael W.Y. Chan. Targeting SMARCAL1 as a therapeutic strategy to enhance cGAS/STING signaling in gastric cancer. [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 6428.