PHGDH inhibition overcomes dabrafenib resistance through metabolic rewiring in BRAF V600E anaplastic thyroid carcinoma

Dabrafenib, a BRAF kinase inhibitor, is used clinically to treat anaplastic thyroid carcinoma (ATC) harboring the BRAF V600E mutation. However, its clinical efficacy is limited due to the rapid emergence of resistance to treatment. In this study, we established a dabrafenib-resistant ATC cell line (8505C-R) and compared its molecular and phenotypic characteristics with those of the parental cells. We evaluated cell proliferation, colony formation, stem cell marker expression, and MAPK pathway activity and identified elevated levels of EGFR and PHGDH in 8505C-R cells as hallmarks of resistance. RNA sequencing revealed that PHGDH inhibition using the selective inhibitor NCT-503 profoundly reprogrammed gene expression networks related to tumor plasticity, stem-like phenotypes, and hyperactivation of the EGFR–MAPK signaling axis. Notably, LRIG1, a negative regulator of EGFR, was differentially expressed upon PHGDH inhibition, suggesting a feedback loop connecting serine metabolism with receptor tyrosine kinase signaling. Functional assays demonstrated that PHGDH inhibition, either alone or in combination with dabrafenib, markedly suppressed colony formation, expression of stemness-associated markers, and MAPK pathway activity. These results reveal a novel resistance mechanism in BRAF-mutant ATCs mediated by PHGDH-dependent serine metabolism and cross-reaction with EGFR–MAPK signaling. Targeting PHGDH effectively suppresses resistance and stemness characteristics, and may provide a novel therapeutic strategy in combination with dabrafenib for aggressive thyroid cancer.