Abstract 6926: Targeting plasma membrane KCa3.1 channels reduces tumor size and mitigates gemcitabine-induced fibrosis in a PDAC mouse model

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer marked by extensive fibrosis and limited therapeutic options. The calcium-activated potassium channel KCa3.1 has been implicated in cancer progression. with Its elevated expression correlatesing with poor survival in PDAC patients. Here, we explored the in vivo therapeutic potential of targeting KCa3.1 channels using selective inhibitors in PDAC. Experimental procedures: Tumor-bearing KPfC (Kraswt/LSL-G12D Tp53fl/+ PDX1Cre+) mice were treated with TRAM-34 or maurotoxin, inhibitors of KCa3.1, either alone or in combination with gemcitabine. KCa3.1 expression, and markers of epithelial-to-mesenchymal transition (EMT) were assessed via immunohistochemistry. Tumor progression was evaluated by histological analysis, measuring tumor node size and Sirius Red staining to quantify fibrosis. Distinct effects of plasma membrane and mitochondrial KCa3.1 inhibition were determined by comparing maurotoxin with the membrane-permeable TRAM-34. Results: KCa3.1 channels were expressed in CK18+ tumor cells and α-SMA+ cancer-associated fibroblasts. Maurotoxin reduced the tumor node size as compared to vehicle treatment, especially in combination with gemcitabine. In contrast, TRAM-34 and gemcitabine in monotherapy showed no significant impact on tumor node size. Gemcitabine alone induced a marked increase in fibrosis within tumor nodes, an effect not observed with other treatments. Notably, co-treatment with KCa3.1 inhibitors prevented gemcitabine-induced fibrosis and reversed EMT marker expression. Conclusions: Selective targeting of plasma membrane KCa3.1 channels with maurotoxin reduces tumor node size and mitigates gemcitabine-induced fibrosis in PDAC. These findings highlight the therapeutic potential of KCa3.1 inhibition as a strategy to enhance the efficacy of gemcitabine and limit desmoplasia. Citation Format: Zoltan Pethö, Ilka Neumann, Weronika Wilczak, Micol Rugi, Sarah Sargin, Sandra Schimmelpfennig, Elke Nass, Gonçalo Mesquita, Dominika Ciechanska, Andrea Oeckinghaus, Serena Pillozzi, Natalia Prevarskaya, V’yacheslav Lehen’kyi, Albrecht Schwab, Benjamin Soret. Targeting plasma membrane KCa3.1 channels reduces tumor size and mitigates gemcitabine-induced fibrosis in a PDAC mouse model [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 6926.