Targeting glycogen synthase kinase-3β in pancreatic ductal adenocarcinoma: Mechanisms and clinical translation

Targeting glycogen synthase kinase-3β (GSK-3β), encoded by GSK3B, offers a strategy for disrupting pancreatic ductal adenocarcinoma (PDAC) survival and treatment adaptation.Experimental studies, including genetic perturbation and patient-derived models, have connected this kinase to replication-stress tolerance, protein turnover, and epithelial plasticity.In experimental PDAC, GSK-3β inhibition can enhance chemotherapy activity through effects on survival transcription and checkpoint signaling; opposing β-catenin and PTEN responses make treatment sensitivity dependent on substrate and cellular context.This review examines the direct PDAC mechanisms, evaluates elraglusib development, and relates drug specificity and candidate biomarkers to patient selection.A randomized phase II trial in previously untreated metastatic PDAC reported longer overall survival with elraglusib plus gemcitabine/nab-paclitaxel, alongside a nonsignificant progression-free-survival difference and greater toxicity.Clinical translation faces three related challenges: Confirming benefit at tolerable chemotherapy exposure, distinguishing kinase inhibition from elraglusib's additional microtubule activity, and identifying treatment-predictive tumor dependencies.Integrating tumor pharmacodynamics with functional models and randomized clinical outcomes could establish when GSK-3β-directed treatment adds value in PDAC and guide the development of rational combinations.