PHGDH Drives 5-FU Chemoresistance in Colorectal Cancer through the Hedgehog signaling

This study investigates the role of phosphoglycerate dehydrogenase (PHGDH) in 5-fluorouracil (5-FU) chemoresistance in colorectal cancer (CRC). The researchers discovered that PHGDH expression is highly variable in tumor tissues and patient-derived CRC organoids, with elevated PHGDH levels correlating with reduced sensitivity to 5-FU treatment. Through transcriptomic analysis, PHGDH was found to promote activation of the Hedgehog (HH) signaling pathway, which plays a key role in chemoresistance. PHGDH silencing reduces HH activation and increases sensitivity to 5-FU, while PHGDH overexpression has the opposite effect. Significantly, combined treatment with 5-FU and HH pathway inhibitors (JC19 or GANT61) synergistically enhances chemosensitivity in high-PHGDH expressing CRC cells, organoids, and xenograft models. This dual-targeting approach effectively limits tumor growth in mice. The findings establish PHGDH as a potential biomarker for predicting response to 5-FU-based chemotherapy and suggest that targeting the PHGDH-HH axis may represent a promising therapeutic strategy to overcome chemoresistance in CRC. Overall design: RNA-seq profiling of wildtype HCT8 colorectal cancer cells and their PHGDH-silenced clones to investigate transcriptomic changes associated with PHGDH silencing and its impact on 5-FU chemoresistance mechanisms.