Extracellular serine transport drives innate resistance to PHGDH inhibitors

PHGDH has been proposed as a cancer dependency in a subset of cancers with high levels of de novo serine synthesis, independent of the availability of extracellular serine. This metabolic non-oncogene addiction implies an inflexibility of cells to adapt to alternative sources of serine. However, upon further examination, using a variety of genetic tools and NAD-competitive inhibitors, potent and durable inhibition of PHGDH enzymatic activity is not sufficient to cause an antiproliferative effect in breast and lung cancer cells. We were unable to find conditions in which PHGDH is required in the presence of extracellular serine, ruling out the possibility of a non-enzymatic basis for PHGDH dependency. A serine metabolism-focused CRISPR screen confirmed the de novo serine synthesis is only required in serine/glycine-deficient media and indicated that no individual transporter or adjacent signaling node could sensitize breast cancer cells to PHGDH inhibition. Extracellular serine availability drives innate resistance to PHGDH inhibitors, limiting the utility of PHGDH as a drug target.