Inhibition of HBP by targeting PGM3 enzyme as new anticancer therapy

N-glycosylation and O-GlcNAcylation aberrant variations in cancer result from an augmented flux through the Hexosamine Biosynthetic Pathway (HBP) and play different roles in tumor progression. Among the different enzymes involved in this pathway, we focused on the N Acetylglucosamine-phosphate Mutase (PGM3) which control both N- and O- Glycosylation and it is downstream to the HBP’s savage pathway. Therefore, we have developed a new PGM3 competitive inhibitor, FR054, and we have investigated the effect of HBP inhibition in breast and pancreatic cancer (PC) cell lines. FR054 induces a dramatic decrease in cell proliferation and survival and a strong reduction of cancer cell adhesion and migration in both type of tumors, and it is well tolerated and suppress tumor growth in in vivo model. The impaired survival of cancer cells upon FR054 treatment is associated with the activation of Unfolding Protein Response (UPR), accumulation of intracellular ROS, inhibition of EGFR signalling, and activation of an apoptotic process. In PC, transcriptional data also indicated an enrichment in phospholipids remodelling and Ferroptosis. We tested the synergistic effect of FR054 in combination with Erastin, known to induce Ferropotosis. Moreover, FR054 is also able to increase the sensitivity of PC cells to gemcitabine treatment. In fact, FR054, inhibiting DNA repair protein O-GlcNAc, negatively regulates DNA damage repair and therefore, when combined with GEM, enhances apoptosis through the prevention of the GEM induced intra-S-phase checkpoint activation. For all this reasons, inhibition of HBP may represent a novel anticancer therapy.