Exploiting DNA damage protein O-glycosylation to enhance chemotherapy in pancreatic cancer

Pancreatic cancer (PC) is the fourth leading cause of cancer death [1]. Presently, chemotherapy based on gemcitabine (GEM) is one of the most widely used schemes for PC, but this standard approach appears poorly effective in patients due to resistance development[2]. GEM-resistance is related to cancer metabolism rewiring. Noteworthy, PC exhibits an increased flux through the Hexosamine Biosynthetic Pathway (HBP), involved in protein glycosylation. Recently, it has emerged that HBP regulates DNA damage response, activating DNA Damage Repair (DDR) mechanisms[3]. The project aims to delineate if HBP inhibition and protein O-glycosylation impact pancreatic cancer chemotherapeutics resistance. To this end, we decided to use FR054, a specific PGM3 inhibitor, combined with GEM. Our preliminary results show that this combined treatment enhances cell death in several PC cells through the induction of cell cycle arrest and an increase in DNA damage. Interestingly, FR054 co-treatment prevents the GEM-induced intra-S-phase checkpoint activation since a significant decrease of CHK1 and CHK2 phosphorylation is observed. These findings suggest a direct role of protein O-GlcNAc in S-phase checkpoint control and in DDR protein function, providing a link between cancer -specific metabolic reprogramming and potential therapeutic response.