Somatic mutation and a gene variation in human lung cancer cells change glycine to cysteine in the KEAP1 DGR domain, introducing local conformational changes that reduce Keap1's affinity for Nrf2.

Keap1 prevents activation of Nrf2 and lung cancer cell growth

Keap1 expression is regulated by an epigenetic mechanism in lung cancer.

Targeting Nrf2 activity in lung cancers, particularly those with Keap1 mutations, could be a promising strategy to inhibit tumor growth and circumvent chemoresistance.

Methylation at the KEAP1 promoter region was detected in 22 out of the 47 non-small cell lung cancer

Genetic disruption of KEAP1/CUL3 E3 ubiquitin ligase complex components is a key mechanism of NF-kappaB pathway activation resulting in lung cancer.

We found a statistically significant correlation between the presence of Keap1/Nrf2 (nuclear factor erythroid-2-related factor 2) mutations and increased multidrug-resistant protein-3 messenger RNA levels in non-small cell lung carcinoma patient samples.

Suppression of KEAP1 in lung tumor cells resulted in increased expression of PPARgamma and was accompanied by induction of cell differentiation markers andattenuated expression of cancer stem cell markers.

KEAP1 mutation is associated with drug resistance in lung cancer.

Data suggest that KEAP1 mutations (such as those observed in lung cancer patients) affect conformation/folding/stability of Keap1 and its binding affinity for ligands NRF2 (nuclear factor erythroid 2-like 2) and PTMA (prothymosin alpha).

Combined genomic and proteomic analyses demonstrated infrequent alteration of validated lung cancer targets but identified novel potential targets for TTF1-negative LUAD, including KEAP1/Nrf2 and DNA repair pathways

The modification of NRF2 or KEAP1 expression in non-small cell lung cancer cell lines disrupted downstream gene expression and cell sensitivity to platinum-based drugs.

Results provide evidence for a critical role of mutations in TP53 and KEAP1 during lung squamous cell carcinoma (LSCC oncogenesis, because deletion of either gene leads to increased self-renewal of airway basal stem cells. Also, KEAP1/NRF2 mutations increase radioresistance and predict local tumor recurrence in radiotherapy treated LSCC patients.

ESI induces protective autophagy of lung cancer cells through Nrf2-p62-keap1 feedback loop

provide a rationale for stratification of human patients with lung cancer harboring KRAS/KEAP1- or KRAS/NRF2-mutant lung tumors as likely to respond to glutaminase inhibition

Data indicate that kelch-Like ECH-associated protein 1 (KEAP1)/nuclear factor (erythroid-derived 2)-like 2 protein (NRF2)-mutant lung cancer is a microenvironmentally distinct, biologically heterogeneous, and clinically underestimated disease.

Results found that KEAP1 mutation was exclusively present in PILAR1 expressing lung Adenocarcinoma (LUAD) samples.

CDO1 is preferentially silenced by promoter methylation in human non-small cell lung cancers (NSCLC) harboring mutations in KEAP1, the negative regulator of NRF2. CDO1 silencing promotes proliferation of NSCLC by limiting the futile metabolism of cysteine to the wasteful and toxic byproducts cysteine sulfinic acid and sulfite (SO3(2-)), and depletion of cellular NADPH.

This is the first study that has described the effects of KEAP1 silencing on the regulation of NRF2 activity in lung carcinoids cells. The epigenetic deregulation of the KEAP1/NRF2 by a KEAP1 promoter hypermethylation system appears to be a frequent event in lung carcinoids.

Our results confirm the effect of methylation on KEAP1 transcription control across multiple histologies of lung cancer and suggest pyrosequencing as the best approach to investigate the pattern of CpGs methylation in the promoter region of KEAP1.

We have demonstrated that FAM129B in cancer promotes Nrf2 activity by reducing its ubiquitination through competition with Nrf2 for Keap1 binding via its DLG and ETGE motifs. In addition, FAM129B reduces chemosensitivity by augmenting Nrf2 antioxidative signaling and confers poor prognosis in breast and lung cancer

mutations in the KEAP1/NFE2L2 pathway occur in approximately 7% of lung adenocarcinomas with activating EGFR mutations at diagnosis. Patients with KEAP1/NFE2L2/CUL3 mutations display relative intrinsic resistance to EGFR TKIs with reduced time to treatment failure.

mutations in the KEAP1 gene are over represented in subset of lung adenocarcinoma that exhibit rapid progression and chemotherapy resistance features.

Role of KEAP1/NFE2L2 mutations in the Chemotherapeutic Response of Patients with Non-Small Cell lung cancer.

MicroRNA-421 confers paclitaxel resistance by binding to the KEAP1 3'UTR and predicts poor survival in non-small cell lung cancer.

Integrated data analysis reveals significant associations of KEAP1 mutations with DNA methylation alterations in lung adenocarcinomas.

KEAP1-driven co-mutations in lung adenocarcinoma unresponsive to immunotherapy despite high tumor mutational burden.