Abstract 1371: ChemoNETosis is associated with chemotherapy resistance in pancreatic cancer

Abstract Background: Chemotherapy resistance is a major contributor of the poor prognosis of pancreatic cancer, yet its underlying mechanisms remain poorly understood. Neutrophil Extracellular Traps (NETs), a form of neutrophil-specific cell death, have been reported to be associated with poor prognosis in various cancers because they act to suppress tumor immunity and promote metastasis. Recently, chemotherapy-stimulated NETs, termed “ChemoNETosis”, were reported to contribute to chemotherapy resistance in breast cancer (Mousset A, Cancer cell. 2023). Therefore, we investigated the role of NETs in resistance to cytotoxic chemotherapy in pancreatic cancer. Methods: The abundance of NETs in the tumor microenvironment was analyzed in relation to chemotherapy efficacy using immunohistochemical staining of resected specimens from pancreatic cancer patients treated with neoadjuvant chemotherapy. The ability of pancreatic cancer cells to induce NETs was assessed with and without gemcitabine stimulation by extracellular DNA staining in vitro and by immunohistochemical analysis in vivo. Finally, the efficacy of the combined anti-NETs treatment and gemcitabine was examined in a mouse subcutaneous tumor model. Results: NETs were more abundant in unresponsive tumors compared to responsive tumors in clinical sample. Gemcitabine-treated pancreatic cancer cells induced significantly higher levels of NETs than untreated cells in vitro as well as in vivo tumor models. This “ChemoNETosis” was effectively inhibited by Navarixin, a CXCR2 inhibitor. Combination therapy with Navarixin and gemcitabine achieved greater tumor reduction compared to gemcitabine alone with, a complete response (CR) rate of 28.6% (2/7) vs 0% (0/7). Conclusion: NETs may play a key role in chemotherapy resistance in pancreatic cancer. Targeting NETs could provide a novel approach to enhancing the efficacy of chemotherapy in preclinical models and warrants further investigation. Citation Format: Shohei Nogi, Shunsuke Kagawa, Atsuki Taniguchi, Nobuhiko Kanaya, Yoshihiko Kakiuchi, Kazuya Yasui, Satoru Kikuchi, Shinji Kuroda, Hiroshi Tazawa, Toshiyoshi Fujiwara. ChemoNETosis is associated with chemotherapy resistance in pancreatic 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 1371.