Targeting purine synthesis in ASS1-expressing tumors enhances the response to immune checkpoint inhibitors

Cancer cell metabolic reprogramming: a keystone for the response to immunotherapy

“…Even if these strategies are currently used for the therapy of numerous cancer types or if emerging strategies specifically targeting purines or pyrimidines appear attractive 99 , there are relatively low amounts of data concerning the potential of targeting purine or pyrimidine metabolism in the context of immunotherapy. However, recent studies have shown that alteration of the urea cycle, which is the main pathway used by mammals to eliminate waste nitrogen, can modulate the response to immunotherapy 100,101 . Indeed, authors have demonstrated that specific alterations in the expression of urea cycle-associated enzymes induce a specific mutation signature due to an increase in the ratio of pyrimidine to purine associated with the expression of hydrophobic tumor antigens and consequently an enhanced response to immune checkpoint blockade.…”

Flexibility and Adaptation of Cancer Cells in a Heterogenous Metabolic Microenvironment

“…The group showed that upon phosphorylation by AKT, PCK1 translocates to the endoplasmic reticulum, where it mediates the GTP-dependent phosphorylation of the regulatory INSIG proteins, with a resulting hyperactivation of sterol regulatory element-binding proteins (SREBPs) and lipogenesis, thereby stimulating tumor growth [ 86 ]. The downstream metabolites generated via PCK1 or PCK2 in glucose-deprived cancer cells include all the biosynthetic precursors classically considered to be derived from glucose: the phospholipid glycerol backbone [ 77 ], serine and glycine used for purine biosynthesis [ 71 , 87 ] and ribose phosphate [ 72 , 73 ] ( Figure 3 ). Thus, PCK1 or PCK2 enable cells to produce gluconeogenic/glycolytic intermediates for biosynthetic pathways that are essential for cancer cell proliferation in the absence of glucose.…”

“…Simultaneous silencing of hypoxia-inducible factors (HIFs), HIF-1α and HIF-2α, has been shown to inhibit low-glucose induced PCK2 expression in normoxia [ 71 ], on the other hand, hypoxia reduced PCK2 protein in lung cancer cells [ 90 ], and PCK2 was found to be inversely correlated with the hypoxia-induced glucose transporter GLUT1 in human lung cancers [ 90 ]. Recently, S-nitrosylation of PCK2 and the upstream enzyme PC ( Figure 2 ) have been described to occur in different cancer cell lines in medium lacking glucose, in a manner dependent on nitric oxide production by the arginine-citrulline cycle [ 87 ]. This post-translational modification enhanced serine, glycine and thereby purine formation from glutamine in glucose-starved cancer cells [ 87 ].…”

“…Recently, S-nitrosylation of PCK2 and the upstream enzyme PC ( Figure 2 ) have been described to occur in different cancer cell lines in medium lacking glucose, in a manner dependent on nitric oxide production by the arginine-citrulline cycle [ 87 ]. This post-translational modification enhanced serine, glycine and thereby purine formation from glutamine in glucose-starved cancer cells [ 87 ]. Thus, oncogenic and nutrient-sensing pathways converge on the regulation of PCK1 and PCK2 in cancer cells, which ensures their flexible expression according to the nutritional state and metabolic demands.…”

PCK2 opposes mitochondrial respiration and maintains the redox balance in starved lung cancer cells

“…PCK2, the prime isoform expressed in lung cancer promotes the survival and proliferation of lung cancer cells under conditions of low glucose, as well as xenograft growth in vivo (Leithner et al , 2015; Leithner et al , 2018; Vincent et al , 2015). In case of low glucose availability, PCK2 mediates the biosynthesis of serine, glycine and purine nucleotides (Keshet et al , 2020; Vincent et al , 2015), or the glycerol backbone of phospholipids (Leithner et al , 2018) in cancer cells.…”