NFE2L2 and cancer: Hyperactivation of NRF2 can occur in cancer cells through diverse mechanisms, including somatic mutations of NFE2L2 (mainly within the DLG and ETGE motifs), KEAP1, or CUL3 genes; transcriptional upregulation of NFE2L2 by oncogenes (e.g., MYC, KRASG12D, and BRAFV619E); accumulation of KEAP1-associated proteins (e.g., p62); and epigenetic alterations of the KEAP1 and NFE2L2 promoters (10, 11).