The NAD ⁺ Salvage Pathway Supports PHGDH-Driven Serine Biosynthesis

NAD ⁺ is a key metabolic redox cofactor that is regenerated from nicotinamide through the NAD ⁺ salvage pathway. Here, we find that inhibiting the NAD ⁺ salvage pathway depletes serine biosynthesis from glucose by impeding the NAD ⁺ -dependent protein, 3-phosphoglycerate dehydrogenase (PHGDH). Importantly, we find that PHGDH ^high breast cancer cell lines are exquisitely sensitive to inhibition of the NAD ⁺ salvage pathway. Further, we find that PHGDH protein levels and those of the rate-limiting enzyme of NAD ⁺ salvage, NAMPT, correlate in ER-negative, basal-like breast cancers. Although NAD ⁺ salvage pathway inhibitors are actively being pursued in cancer treatment, their efficacy has been poor, and our findings suggest that they may be effective for PHGDH-dependent cancers. Subsets of breast cancers depend on the serine biosynthesis enzyme PHGDH. Murphy et al. show that NAD ⁺ used for PHGDH function requires the NAD ⁺ salvage pathway and that PHGDH-dependent cancers are, thus, sensitive to NAD ⁺ salvage inhibitors. Serine biosynthesis and NAD ⁺ salvage pathway enzymes are also commonly co-expressed in breast cancers.