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Updated: Jul 31, 2025

Analyzing Tumor Gene Expression Factors with the CorExplorer Web Portal
Published on: October 11, 2019
A core NRF2 gene set defined through comprehensive transcriptomic analysis predicts selective drug resistance and
Abstract:
The NRF2-KEAP1 pathway plays an important role in the cellular response to oxidative stress but may also contribute to metabolic changes and drug resistance in cancer. We investigated the activation of NRF2 in human cancers and fibroblast cells through KEAP1 inhibition and cancer associated KEAP1/NRF2 mutations. We define a core set of 14 upregulated NRF2 target genes from seven RNA-Sequencing databases that we generated and analyzed, which we validated this gene set through analyses of published databases and gene sets. An NRF2 activity score based on expression of these core target genes correlates with resistance to drugs such as PX-12 and necrosulfonamide but not to paclitaxel or bardoxolone methyl. We validated these findings and also found NRF2 activation led to radioresistance in cancer cell lines. Finally, our NRF2 score is prognostic for cancer survival and validated in additional independent cohorts for novel cancers types not associated with NRF2-KEAP1 mutations. These analyses define a core NRF2 gene set that is robust, versatile, and useful as a NRF2 biomarker and for predicting drug resistance and cancer prognosis.
Insights
The NRF2-KEAP1 pathway impacts cancer
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- The NRF2-KEAP1 pathway is crucial for cellular oxidative stress response.
- This pathway's dysregulation is implicated in cancer's metabolic shifts and drug resistance.
Approach:
- Investigated NRF2 activation in human cancers and fibroblasts via KEAP1 inhibition and mutations.
- Defined and validated a core set of 14 NRF2 target genes using RNA-sequencing data.
- Developed an NRF2 activity score based on target gene expression.
Key Points:
- NRF2 activity score correlates with resistance to specific drugs (PX-12, necrosulfonamide) and radioresistance.
- The score does not predict resistance to paclitaxel or bardoxolone methyl.
- NRF2 activation is linked to radioresistance in cancer cell lines.
Conclusions:
- A core NRF2 gene set serves as a versatile biomarker.
- The NRF2 score predicts drug resistance and cancer prognosis, even in cancers without NRF2-KEAP1 mutations.
- This biomarker is robust and prognostic across diverse cancer types.
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