PGK1/PHGDH axis drives radioresistance in glioblastoma stem cells

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, and radiotherapy is a key treatment option. However, glioblastoma stem cells (GSCs) can develop resistance to radiotherapy through metabolic reprogramming, which often results in tumor recurrence. Here we found that glycolytic enzyme phosphoglycerate kinase 1 (PGK1) was phosphorylated at threonine 8 (T8) by ataxia telangiectasia mutated (ATM) upon irradiation (IR), leading to enhanced binding of PGK1 to phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme for the serine synthesis pathway (SSP). PGK1 subsequently functioned as a protein kinase to phosphorylate PHGDH at T60, which resulted in enhanced PHGDH enzymatic activity and increased serine synthesis to fuel the production of S-adenosylmethionine (SAM). Increased SAM then promoted the levels of histone H3K36 trimethylation (H3K36me3) to recruit RAD51 to engage homologous recombination (HR)-mediated DNA damage repair to confer resistance of GSCs to IR. Importantly, both inhibiting PHGDH T60 phosphorylation and suppressing its enzymatic activity sensitized GSCs to IR, inhibited growth of orthotopich xenografts, and prolonged survival of tumor-bearing mice. Furthermore, clinical analysis indicated that phosphorylation levels at both PHGDH T60 and PGK1 T8 corresponded closely with the poor prognosis of GBM patients. This study revealed an ATM-PGK1-PHGDH signaling axis that promoted serine synthesis to confer resistance of GSCs to IR, and suggested that targeting PHGDH may serve as a potential strategy to overcome radioresistance in GBM.