PGM3 Inhibition as a Novel Strategy to Induce BRCAness in HR-Proficient Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, with limited therapeutic options and frequent resistance to gemcitabine (GEM). Metabolic rewiring via the Hexosamine Biosynthetic Pathway (HBP) supports tumor growth and chemoresistance through aberrant glycosylation and modulation of the DNA damage response. Phosphoglucomutase 3 (PGM3), a key HBP enzyme, correlates with poor prognosis and GEM resistance. We investigated FR054, a novel PGM3 inhibitor, in PDAC models. FR054 reduced proliferation, migration, and tumor growth, and synergized with GEM to increase DNA damage and apoptosis. Mechanistically, FR054 impaired ATR/ATM expression, compromised DNA repair checkpoints, and reduced homologous recombination efficiency, inducing a BRCAness phenotype in HR-proficient cells. Targeting PGM3 thus represents a promising strategy to enhance GEM efficacy and overcome resistance in PDAC.