Targeting Hexosamine Biosynthetic Pathway to Overcome Resistance in Pancreatic Cancer Treatment

Pancreatic cancer (PC) is the seventh leading cause of cancer deaths, with nearly 80% diagnosed at advanced stages. Gemcitabine (GEM) is the primary treatment, but resistance necessitates alternative therapies. PC's metabolic changes upregulate the Hexosamine Biosynthetic Pathway (HBP), producing UDP-N acetylglucosamine for protein glycosylation. FR054, a small-molecule inhibitor of PGM3 (an HBP enzyme), impairs cancer cell survival by activating the unfolded protein response, increasing ROS, and initiating apoptosis. Combining GEM with FR054 is well tolerated and nearly halts tumor growth in xenograft and patient derived xenograft (PDX) models. FR054 enhances GEM's efficacy by promoting apoptosis through increased DNA damage and altered DDR protein phosphorylation. This study supports exploring HBP inhibitors to improve chemotherapeutic efficacy and overcome PC chemoresistance.