Protein phosphatase 2A as a therapeutic target in pancreatic cancer: past insights, recent advances, and future directions

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an 8% five-year survival rate. KRAS, the major oncogenic driver, triggers several phosphorylation cascades, making phosphatases, particularly protein phosphatase 2A (PP2A), which accounts for 50–70% of cellular phosphatase activity, a critical regulator. Through association with multiple regulatory subunits, PP2A modulates both tumor-suppressive and tumor-promoting functions. The tumor-suppressive function is often inhibited in PDAC by endogenous inhibitors like SET and CIP2A, which are frequently upregulated. This review examines the multifaceted roles of PP2A in PDAC, with a focus on its published roles in KRAS-MYC signaling, DNA damage response, and epithelial-to-mesenchymal transition, as well as current and emerging therapeutic strategies aimed at modulating PP2A activity.