Abstract 5630: Ecubectedin as a promising therapeutic agent against gastric cancer through WNT/β-Catenin modulation

Gastric cancer continues to be a major global health challenge due to its high mortality rate, with over half of patients showing significant dysregulation of the WNT/β-catenin pathway. Ecubectedin, a novel transcriptional inhibitor, has shown potent antiproliferative effects across several solid tumors. The aim of this study was to characterize the molecular effects of ecubectedin in gastric cancer, both in vitro and in vivo, focusing on transcriptomic analysis of key regulatory pathways. Ecubectedin´s antineoplastic activity was evaluated through MTT assays in a representative panel of 15 gastric cancer cell lines. Eight cell lines were chosen to assess the effects of ecubectedin on the transcriptome following a 6-hour exposure to 50 nM. Ecubectedin´s in vivo antitumor effects were evaluated in HGC-27 xenograft mouse models. Ecubectedin demonstrated potent antitumor activity in vitro, with GI50 values in the low nanomolar range (from 0.3 to 8 nM). Ecubectedin exerts a potent effect as a transcription inhibitor, leading to significant repression of 2,775 genes. Gene set enrichment analysis revealed that Ecubectedin disrupted key signaling pathways, especially WNT/β-catenin. At the protein level, Ecubectedin (50 nM) modulated the WNT/β-catenin pathway and inhibited TCF/β-catenin-mediated transcription. In vivo, a single i.v. dose of Ecubectedin (0.6 mg/kg) inhibited tumor growth by 61% after 7 days in both RNA-seq and in vivo protein data (from tumors in ecubectedin-treated mice) support that ecubectedin represses WNT/β-catenin signaling. In conclusion, ecubectedin shows strong antitumor activity against gastric cancer, modulating the often-dysregulated WNT/β-catenin pathway, highlighting its potential as a promising therapeutic for further clinical exploration. Citation Format: Alejandro Losada, Marta Martínez Diez, Eugenio Bustos-Morán, Ismael Fernández-Miranda, Maria José Guillen, Pablo M. Avilés, Marcelo Lima Ribeiro, Carmen Cuevas. Ecubectedin as a promising therapeutic agent against gastric cancer through WNT/β-Catenin modulation [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 5630.