Hexosamine Biosynthetic Pathway inhibition cooperates with gemcitabine inducing in vitro and in vivo pancreatic cancer regression by enhancing DNA damage

Pancreatic cancer (PC) ranks as the seventh leading cause of oncological deaths, with nearly 80% of patients diagnosed at advanced stages. Despite chemotherapy based on gemcitabine (GEM) serving as the primary treatment, PC frequently develops resistance to GEM, necessitating the exploration of alternative therapies. PC's metabolic alterations induce upregulation of the Hexosamine Biosynthetic Pathway (HBP), which produces UDP-N-acetylglucosamine crucial for protein glycosylation. Recent studies highlight the efficacy of FR054, a small-molecule inhibitor of PGM3, an HBP enzyme, in impairing cancer cell survival. This impairment is linked to activation of the unfolded protein response, accumulation of intracellular ROS, and initiation of apoptotic and non-apoptotic processes, confirming HBP's critical role in PC survival. In vivo, experiments demonstrate that combining GEM with FR054 is well tolerated and nearly completely suppresses tumor growth in xenograft and patient-derived xenograft (PDX) mouse models. Metabolic pathways, including HBP, significantly influence DNA Damage Repair (DDR) by regulating substrate availability and the function of key DDR players. This study shows that FR054 enhances GEM’s efficacy by promoting apoptosis through increased DNA damage and significant changes in the phosphorylation status of several DDR proteins. Proteomics analysis reveals O-glycosylation of some DDR-involved proteins, highlighting the correlation between protein glycosylation and DDR. In conclusion, the findings underscore HBP's potential role in regulating cancer progression. The synergistic effect of FR054 and GEM presents a promising approach to overcoming chemoresistance in PC. This study supports further investigation of HBP inhibitors as novel anticancer strategies, particularly in enhancing the efficacy of existing chemotherapeutic agents like GEM.