A PHGDH–Hedgehog Axis Drives 5-FU Chemoresistance in Colorectal Cancer

Phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in the de novo serine synthesis pathway (SSP), a highly regulated pathway overexpressed in several cancer types. It has been shown that high PHGDH levels correlate with accelerated proliferation of different tumor cells, while its depletion shows selective toxicity. Recently, it has emerged that PHGDH expression is dynamically regulated during different stages of tumor progression, promoting cancer aggressiveness. Results show that the expression level of PHGDH is heterogeneous in colorectal cancer (CRC) cell lines and in tumor samples from CRC patients and correlates with aggressiveness and resistance of CRC cell lines to 5-Fluorouracil (5-FU) treatment. Furthermore, PHGDH expression correlates with upregulation of Hedgehog (HH) pathway, conferring resistance to 5-FU treatment. The combination of 5-FU and JC19, a GLI1 inhibitor, is able to enhance the chemo-sensitivity both in vitro (cells and organoids) and in vivo (mouse models).