Pyrimethamine Restores KEAP1-Mediated Degradation of Select NRF2 Mutants in Esophageal Squamous Cell Carcinoma
Zhaohui Xiong·Xiaoxin Chen·Haining Wang·Boopathi Subramaniyan·Candice Bui-Linh·Yahui Li·Huan Li·Michael C. Wang·Francis Spitz·Chorlada Paiboonrungruang
Background: Esophageal squamous cell carcinoma (ESCC) remains a highly lethal malignancy with limited therapeutic options, in part due to frequent activation of nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2). Gain-of-function mutations in NRF2 disrupt its negative regulation by Kelch-like ECH-associated protein 1 (KEAP1), resulting in sustained NRF2 signaling that promotes tumor growth and resistance to chemotherapy and radiation. We previously identified the FDA-approved drug pyri