Abstract 2550: Chemotherapy-induced senescence of cancer-associated fibroblasts promotes gastric cancer progression and resistance to chemotherapy

Abstract Purpose: Chemotherapies for patients with gastric cancers (GCs) has been shown disappointing results in the clinics. The cancer-associated fibroblasts (CAFs) could be considered one cause of the resistance to chemotherapy in GCs. However, the chemotherapy-induced reprogramming of CAFs and its effects on GC progression and the resistance to chemotherapy has not been elucidated. Methods: IncuCyte and transcriptome were used to identify chemotherapy-induced senescence of CAFs. Screening for drugs to inhibit senescence of CAFs was performed. The cell proliferation and migration assays and phospho-protein array were performed to investigate the effects of senescent CAFs on GC cells. Inhibitory effects of screened drugs on CAFs were also evaluated in experimental models. Senescent CAFs and their clinical meanings were also investigated in the human GC tissues undergoing preoperative chemotherapies. Results: Chemotherapy could alleviate proliferation and widen cytoplasm of CAFs. Some secretory molecules like TNF-α were upregulated in the CAFs with chemotherapy. Chemotherapy-treated CAFs increased the resistance to chemotherapy and the migratory potentials of GC cells. The COX2 inhibitor, one of the screened drugs, has inhibitory effect on chemotherapy-induced senescence CAFs. Consequently, it could suppress GC progression and resistance to chemotherapy. The GC patients with senescent CAFs were significantly correlated with poor histologic response to chemotherapy. Conclusions: In this study, we are convinced that the chemotherapy-induced senescence of CAFs could have a significant effect on progression and resistance to chemotherapy in GC. Inhibitory drugs for chemotherapy-induced senescence of CAFs could be used to overcome the CAF-induced resistance to the chemotherapy in GCs. Citation Format: In-Hye Ham, Yulim Lee, Hur Hoon. Chemotherapy-induced senescence of cancer-associated fibroblasts promotes gastric cancer progression and resistance to chemotherapy [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 2550.