NFE2L2

Overview

NFE2L2 (NRF2) is a transcription factor that is the master regulator of the cellular antioxidant response. In cancer, activating mutations in NFE2L2 — particularly at the DLG and ETGE motifs that mediate KEAP1-mediated degradation — lead to constitutive NRF2 activity, promoting oxidative stress resistance and contributing to chemotherapy resistance. NFE2L2 mutations are enriched in lung squamous cell carcinoma and are mutually exclusive with loss-of-function mutations in KEAP1, its negative regulator.

Alterations observed in the corpus

  • Activating mutations at DLG/ETGE motifs identified as part of the 34% oxidative stress pathway alteration rate in lung squamous cell carcinoma (TCGA, 178 tumors) PMID:22960745
  • Mutations are mutually exclusive with KEAP1 loss-of-function mutations PMID:22960745
  • Deleterious missense mutations in the Neh2 domain in 11 tumors (8%) of muscle-invasive bladder carcinoma; mutually exclusive with TXNIP mutations; mutant tumors upregulated genotoxic-metabolism and ROS-response genes PMID:24476821
  • NFE2L2 is mutated in ESCC as part of the canonical genomic landscape cited in a review of oral microbiome associations with ESCC PMID:24670651
  • NFE2L2 is identified as a driver linked to oxidative-stress signaling in HCC by integrated genomic analysis PMID:24735922
  • Implicated in HCC genomic landscape analysis as part of the broader trunk-mutation set; RAS pathway (KRAS/NRAS) mutations are rare (~1% each) in HCC, with NFE2L2 noted among recurrently altered cancer-related genes PMID:24798001
  • Absent in 39-case aggressive cutaneous squamous cell carcinoma (cSCC) cohort — explicit negative finding suggesting NFE2L2 mutations are not a driver in aggressive cSCC PMID:25303977
  • NFE2L2 significantly mutated in 6% of HNSC (MutSigCV q<0.1, TCGA n=279); activating mutations; co-occurs with KEAP1 and CUL3 in classical mRNA subtype (tobacco-associated, laryngeal sub-site), paralleling LUSC. PMID:25631445
  • In HCC, NFE2L2 and KEAP1 are both significantly mutated components of the oxidative-stress pathway (altered in 12% combined); NFE2L2-mutant HCC shows elevated NQO1 expression and may be sensitive to HSP90 inhibitors (17-AAG/17-DMAG), modulated by NQO1 P187S (rs1800566) variant. PMID:25822088
  • NFE2L2 significantly mutated in lung squamous cell carcinoma but not other cancer types (excluding HNSC, BLCA) in pan-lung cancer TCGA analysis (n=1144) PMID:27158780
  • Significantly mutated in ESCC (especially ESCC1 subtype); 24% mutation frequency in Vietnamese cohort vs 6% in other cohorts (P=0.017); activates the NRF2 pathway and is associated with chemoradiotherapy resistance PMID:28052061
  • Mutations in 2.9% (3/103) of unmatched driver (UMD) LUAD samples; KEAP1 missense variants cluster in the Kelch domain that interacts with NFE2L2/Nrf2, implicating this oxidative-stress pathway in UMD lung adenocarcinoma PMID:28336552

Cancer types (linked)

  • LUSC: Activating mutations at DLG/ETGE Kelch-binding motifs; part of a broader 34% oxidative stress pathway alteration rate; mutually exclusive with KEAP1 mutations PMID:22960745

Co-occurrence and mutual exclusivity

  • Mutually exclusive with KEAP1 loss-of-function mutations (both inactivate the same KEAP1-NRF2 regulatory axis) PMID:22960745

Therapeutic relevance

  • NFE2L2 activation confers resistance to platinum-based chemotherapy; no direct NFE2L2 inhibitor is approved.

Open questions

  • Whether NFE2L2 activation status predicts response to immunotherapy in LUSC remains an open question.

Sources

  • PMID:22960745 — TCGA lung squamous cell carcinoma, 178 tumors

This page was processed by crosslinker on 2026-05-14. - PMID:24476821

This page was processed by crosslinker on 2026-05-14. - PMID:24670651

This page was processed by crosslinker on 2026-05-14. - PMID:24735922

This page was processed by crosslinker on 2026-05-14. - PMID:24798001

This page was processed by crosslinker on 2026-05-14. - PMID:25303977

This page was processed by crosslinker on 2026-05-14. - PMID:25631445

This page was processed by crosslinker on 2026-05-14. - PMID:25822088

This page was processed by crosslinker on 2026-05-14. - PMID:27158780

This page was processed by entity-page-writer on 2026-05-15. - PMID:28336552

This page was processed by wiki-cli on 2026-05-14.