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Pancreatic ductal adenocarcinoma (PDAC) is highly malignant, with a 5-year survival rate of less than 10%. Furthermore, the acquisition of anticancer drug resistance makes PDAC treatment difficult. We established MIA-GEM cells, a PDAC cell line resistant to gemcitabine (GEM), a first-line anticancer drug, using the human PDAC cell line—MIA-PaCa-2. Microtubule-associated serine/threonine kinase-4 (<i>MAST4</i>) expression was increased in MIA-GEM cells compared with the parent cell line. Through inhibitor screening, dysregulated AKT signaling was identified in MIA-GEM cells with overexpression of AKT3. <i>MAST4</i> knockdown effectively suppressed AKT3 overexpression, and both <i>MAST4</i> and AKT3 translocation into the nucleus, phosphorylating forkhead box O3a (FOXO3) in MIA-GEM cells. Modulating FOXO3 target gene expression in these cells inhibited apoptosis while promoting stemness and proliferation. Notably, nuclear <i>MAST4</i> demonstrated higher expression in GEM-resistant PDAC cases compared with that in the GEM-sensitive cases. Elevated <i>MAST4</i> expression correlated with a poorer prognosis in PDAC. Consequently, nuclear <i>MAST4</i> emerges as a potential marker for GEM resistance and poor prognosis, representing a novel therapeutic target for PDAC.