Targeting NRF2 addiction in cancer: synthetic lethal strategies beyond direct inhibition (opens in new tab)

Nuclear factor erythroid 2-related factor 2 (NRF2) (encoded by NFE2L2) is a master regulator of antioxidant, metabolic, and proteostasis pathways. While protective in normal cells, constitutive NRF2 activation driven by loss-of-function mutations in KEAP1, gain-of-function mutations in NFE2L2, or non-mutational mechanisms is common in cancer, occurring in approximately 20%–30% of non-small cell lung cancers and at significant frequencies across multiple tumor types. In cancer, the NRF2 transc...