Abstract 1670: The SHMT inhibitor SHIN1 augments the antitumor efficacy of 5-Fuin preclinical models of gastric cancer

Abstract Advanced gastric cancer (GC) is a malignant tumor with poor prognosis, which requires in-depth exploration of its malignant progression mechanism and the development of efficient therapeutic protocols. Serine hydroxymethyltransferase (SHMT), an important hub in serine-glycine-nucleotide metabolic pathways, plays a crucial role in the occurrence and progression of GC. Bioinformatics analysis and cytological experiments preliminary identified the important role of SHMTs in GC. Drug synergistic screening assays were used to build the therapeutic model in the study. The transcriptomic analysis was performed to clarify the underlying mechanism of combination treatment. Here, we found that the SHMT1 and SHMT2 promoted malignant progression and 5-Fu resistance on GC, and their targeted inhibitor SHIN1 is a promising antitumor drug for GC. The synergistic screening analysis showed that SHIN1 was an efficient synergist for 5-Fu, and combination therapy, alleviated 5-Fu resistance to GC. Mechanistically, The combination treatment induces cell cycle arrest, DNA damage and cellular senescence through the activation of the P53 signaling pathway. These unique characteristics of cell growth inhibition, which are induced via interfering with nucleotide synthesis, were validated by substantial in vitro and in vivo assays. The regimen of SHIN1 combination with 5-Fu may be an efficient preclinical model for the treatment of GC. Citation Format: Huan Deng, Yajie Wang, Lin Xiao, Yisheng Pan. The SHMT inhibitor SHIN1 augments the antitumor efficacy of 5-Fuin preclinical models of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1670.