PGM3 inhibition shows cooperative effects with Erastin inducing pancreatic cancer cell death via activation of the Unfolded Protein Response

Pancreatic ductal adenocarcinoma (PDAC) presents a formidable clinical challenge due to its aggressiveness and resistance to treatment. Notably, PDAC exhibits a pronounced resistance to various therapeutic modalities, often attributed to a wide metabolic reprogramming involving also the Hexosamine Biosynthetic Pathway (HBP). Transcriptional and bioinformatics analyses, performed under inhibition of HBP in PDAC cell models, indicated that activation of ER stress and Unfolded Protein Response (UPR), due to HBP inhibition, activates an NRF2-dependent antioxidative response, characterized by activation of several genes involved in glutathione (GSH) metabolism. Indeed, inhibition of both HBP and the xCT protein, the cystine/glutamate antiporter involved in GSH synthesis, in PDAC cells significantly reduced cell proliferation, enhanced cell death, altered cellular redox status, heightened sensitivity to oxidative stress, increased dependence on glutamine metabolism, and induced ferroptosis. These findings underscore the potential of HBP inhibition to synergize with ERA, offering a promising therapeutic strategy for managing PDAC.