Targeting DHFR to suppress one-carbon metabolism and enhance radiation sensitivity in patients with NRF2-active head and neck squamous cell carcinoma.

WCDD115 radiosensitizes NRF2-competent head and neck squamous cell carcinoma by suppressing one-carbon metabolism and nucleotide biosynthesis, enhancing radiation-induced DNA damage.

• Why it matters: NRF2 hyperactivity in HNSCC is linked to radiation resistance, creating a need for targeted strategies that disrupt tumor metabolic programs supporting survival after irradiation.
• What they did: Preclinical work in NRF2-competent and deficient HNSCC models used clonogenic assays, transcriptomics, metabolomics, and PK/toxicity testing, with correlative mass spectrometry and western blotting. In an open-label window-of-opportunity trial (NCT05678348), previously untreated HPV(-) stage III/IV patients received pyrimethamine 50mg prior to surgery.
• The result: In mice, WCDD115 enhanced radiation efficacy in NRF2-competent but not NRF2-deficient tumors; in patients, DHFR protein increased post-treatment by a mean fold change of 9.91 (95% CI 8.1 to 12.2) with no drug-related grade 3-5 adverse events or surgical delays.

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