Abstract 4102: N6-methyladenosine modification of FZR1 mRNA promotes gemcitabine resistance in pancreatic cancer

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a 5-year survival rate of less than 10% and limited treatment options. Gemcitabine, a pyrimidine nucleoside analogue, is the standard first-line treatment for pancreatic cancer. However, drug resistance to gemcitabine remains a major challenge in PDAC. Dysregulation of N6-methyladenosine (m6A) modification has been linked to human disease regulation, and targeting aberrant m6A modifications or their key regulators may be beneficial to overcome drug resistance. However, the potential role and precise mechanism of m6A modification in the development of gemcitabine resistance in PDAC have not been fully elucidated. Methods: In this study, we screened gemcitabine-insensitive and -sensitive PDAC cells through exposure to time- and dose-gradient gemcitabine. We then performed m6A-sequencing analysis on these cells and identified the hyper-m6A modification of FZR1 as a key molecular event contributing to gemcitabine insensitivity in PDAC. Additionally, we examined human PDAC samples using m6A-qPCR assays and reaved that FZR1 m6A modification had a significant clinical PDAC diagnosis and therapeutic value for PDAC. Results: We found that PDAC cells with distinct gemcitabine sensitivity showed different m6A profiles and that FZR1 had the most upregulated m6A modification in gemcitabine-insensitive cells compared with gemcitabine-sensitive cells. Mechanistically, we discovered that RNA m6A modification enhanced FZR1 translation in a GEMIN5-dependent manner, leading to a gemcitabine-insensitive phenotype by inducing a quiescent state. Importantly, targeting the m6A modification of FZR1 increased the sensitivity of PDAC cells to gemcitabine both in vitro and in vivo. Conclusions: This study identified the m6A-FZR1 axis as an underlying mechanism contributing to gemcitabine treatment resistance in pancreatic cancer. The m6A-FZR1 axis may serve as a predictor of gemcitabine treatment response in patients with PDAC. Overall, our discoveries interestingly link the dysregulated m6A modification to gemcitabine insensitivity in PDAC, and provide new insights into the molecular mechanisms of gemcitabine resistance in this cancer type. Citation Format: Ziming Chen. N6-methyladenosine modification of FZR1 mRNA promotes gemcitabine 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 4102.