LAUSR

Redox status is a main indicator of cancer cell adaptation to chemotherapy. Nuclear factor erythroid 2-related factor 2 (Nrf2) is one of the crucial regulators of redox condition and can affected to drug resistance through redox imbalance. The incidence and mortality of pancreatic cancer (PC) have been gradually increasing globally. Although the first line treatment with anticancer agents improves the disease status, acquired drug resistance is major huddles in the treatment failure. Targeting Nrf2 has been suggested as a promising therapeutic approach for the overcoming drug resistance. In the present study, Nrf2 was found to be upregulated in tumor tissues and gemcitabine-resistant PC cells. In addition, Nrf2 knockdown exhibited to recover gemcitabine sensitivity in the gemcitabine-resistant PC cells. To further validate the role of Nrf2 in gemcitabine-resistant cells, the effects of Nrf2 inhibitor, periplocin, were employed. Periplocin exerted the antiproliferative activities by regulating Nrf2 suppression which leads to the increase of reactive oxygen species generation. Furthermore, the downregulation of Nrf2 by periplocin was correlated to Keap1-mediated protein degradation. Docking simulation also confirmed the binding interaction of Nrf2 and Keap1 by periplocin. These findings suggest that targeting the Nrf2 might be a therapeutic strategy for overcoming acquired gemcitabine PC. Keywords: Pancreatic cancer cell, Gemcitabine resistance, Nuclear factor erythroid-2-related factor 2 (Nrf2), Kelch Like ECH Associated Protein 1 (Keap1), protein degradation Acknowledgements: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2022R1I1A1A01063346). Citation Format: Sang Kook Lee, Eun Seo Bae, Woong Sub Byun, Chae Won Ock, Won Kyung Kim, Hyen Joo Park. Targeting Nrf2 signaling pathway by Keap1-mediated degradation in acquired gemcitabine resistant pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2787.