Metabolic Plasticity in Cancer Cells: Metabolic rewiring is a key feature of cancer cells that promotes survival under adverse conditions and can be exploited as a therapeutic vulnerability. Cancer cells manipulate their metabolic profile to meet the dynamic energy requirements of the tumor microenvironment. The two main metabolic pathways cancer cells use to derive energy from glucose, glycolysis and oxidative phosphorylation, are preferentially and plastically utilized by cancer cells depending on both their intrinsic metabolic properties and their surrounding environment. For example, the metabolic state of cancer cells can be influenced by driver mutations, such as those found in the BRCA1/2 genes, which can determine susceptibility to therapy. Mutations in these genes are particularly prevalent in ovarian and breast cancers. The BRCA1 and BRCA2 genes code for proteins involved in the repair of DNA double-strand breaks, a particularly severe form of DNA damage. When these genes are mutated, cells are less able to repair damaged DNA, promoting the development of cancers.
These “features” unfold new metabolic vulnerabilities that have been explored, with potential targets identified as an increased dependency on OXPHOS for energy production. Similarly, the provision of Nicotinamide Adenine Dinucleotide (NAD), a crucial coenzyme in various metabolic reactions including OXPHOS, could be another potential therapeutic target. Inhibitors of poly (ADP-ribose) polymerase (PARP), which is involved in DNA repair, have shown promising activity in both hereditary BRCA1/2-mutated and sporadic breast and ovarian cancers.
These findings suggest that BRCA-mutant cells heavily rely on OXPHOS and NAD provision, which we have exploited for therapeutic purposes in a preclinical setting.