LAUSR

Simple Summary NRF2-activated or NRF2-addicted cancers show high incidence, especially in esophageal squamous cell carcinoma (ESCC). ESCC with high NRF2 expression is largely resistant to the current major treatments for ESCC and therefore shows a very poor prognosis. In order to develop effective treatments for NRF2-addicted esophageal cancers, the elucidation and understanding of the mechanistic basis of NRF2 function in NRF2-addicted cancer cells are critically important. This review summarizes the current knowledge of the KEAP1-NRF2 system and proposes three distinct approaches for the treatment of NRF2-addicted ESCC. Abstract NRF2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that regulates the expression of many cytoprotective genes. NRF2 activation is mainly regulated by KEAP1 (kelch-like ECH-associated protein 1) through ubiquitination and proteasome degradation. Esophageal cancer is classified histologically into two major types: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC harbors more genetic alterations in the KEAP-NRF2 system than EAC does, which results in NRF2 activation in these cancers. NRF2-addicted ESCC exhibits increased malignancy and acquisition of resistance to chemoradiotherapy. Therefore, it has been recognized that the development of drugs targeting the KEAP1-NRF2 system based on the molecular dissection of NRF2 function is important and urgent for the treatment of ESCC, along with efficient clinical screening for NRF2-addicted ESCC patients. Recently, the fate of NRF2-activated cells in esophageal tissues, which was under the influence of strong cell competition, and its relationship to the pathogenesis of ESCC, was clarified. In this review, we will summarize the current knowledge of the KEAP1-NRF2 system and the treatment of ESCC. We propose three main strategies for the treatment of NRF2-addicted cancer: (1) NRF2 inhibitors, (2) synthetic lethal drugs for NRF2-addicted cancers, and (3) NRF2 inducers of the host defense system.