Hexosamine Biosynthetic Pathway inhibition sensitizes pancreatic cancer cells to DNA damage

Pancreatic cancer (PC) remains a leading cause of cancer-related deaths, with most patients diagnosed at advanced stages and resistant to gemcitabine (GEM) chemotherapy. Emerging evidence highlights the critical role of metabolic reprogramming, particularly altered glucose metabolism, in driving tumor growth, survival, metastasis, and chemoresistance in cancer cells. A key pathway involved is the Hexosamine Biosynthetic Pathway (HBP), which produces UDP-N-Acetylglucosamine (UDP-GlcNAc), a metabolite essential for protein glycosylation. Aberrant glycosylation is implicated in various diseases, including cancer. This study investigates FR054, a novel inhibitor of the HBP enzyme PGM3, demonstrating potent anti-cancer effects both in vitro and in vivo. FR054 disrupts key cancer hallmarks, including homologous recombination, inducing a Brcaness phenotype, and underscores HBP inhibition as a promising therapeutic strategy for cancer treatment