Targeting Hexosamine Biosynthetic Pathway to Overcome Resistance in Pancreatic Cancer Treatment

Pancreatic ductal adenocarcinoma (PDAC), a leading cause of cancer-related deaths, exhibits notable resistance to Gemcitabine (GEM) chemotherapy, attributed to metabolic adaptations, particularly the enhanced flux in the Hexosamine Biosynthetic Pathway (HBP). So, we showed that HBP inhibition with FR054, a PGM3 inhibitor, synergistically enhances PDAC cell death with GEM, inducing apoptosis while attenuating GEM-induced checkpoints activation, thereby countering chemotherapy resistance. Moreover, transcriptional analysis reveals increased reliance on glutathione synthesis and activation of stress response pathways in FR054-treated PDAC cells. Indeed, combined treatment with Erastin causes a synthetic lethality, offering insights into therapeutic strategies for PDAC.