AURKA promotes radioresistance in pancreatic cancer via GSK3β-mediated PTEN phosphorylation at T366

Radioresistance is a major therapeutic challenge in clinical management of pancreatic ductal adenocarcinoma (PDAC), yet the molecular mechanisms governing this process remain largely elusive. In this study, it was demonstrated that the oncogenic kinase Aurora Kinase A (AURKA) drove radioresistance by orchestrating a signaling cascade that inhibited the tumor suppressor PTEN. Analysis of patient cohorts and TCGA data revealed that AURKA was overexpressed in PDAC, and its expression levels were found to robustly correlate with poor patient prognosis. Functionally, AURKA overexpression conferred potent radioresistance, yielding SER values of 0.847 ± 0.086 and 0.824 ± 0.073 in PANC-1 and SW1990 cells, respectively. AURKA overexpression not only markedly enhanced cellular proliferation and migration but also significantly suppressed apoptosis. Mechanistically, Co-IP uncovered that AURKA physically interacted with Glycogen Synthase Kinase 3β (GSK3β). This interaction facilitated the inhibitory phosphorylation of the tumor suppressor PTEN at Threonine 366, which impaired PTEN's phosphatase activity and led to sustained activation of the pro-survival PI3K/AKT/mTOR pathway. Critically, this radioresistant phenotype was reversed by either GSK3β knockdown or the expression of a phosphorylation-deficient PTEN-T366A mutant, confirming the essentiality of this signaling axis. Collectively, this study discovered a novel and clinically relevant AURKA-GSK3β-PTEN signaling axis that mechanistically linked AURKA overexpression to radioresistance in PDAC. Furthermore, our findings provide a strong mechanistic rationale for targeting AURKA, revealing a promising therapeutic strategy to overcome radioresistance and improve therapeutic outcomes in pancreatic cancer.