A Core NRF2 Gene Set Defined Through Comprehensive Transcriptomic Analysis Predicts Selective Drug Resistance and...

Area of Science:

• Molecular Biology
• Cancer Research
• Genomics

Background:

• The NRF2-KEAP1 pathway regulates oxidative stress response but is implicated in cancer progression and drug resistance.
• Current methods for defining NRF2 target genes lack context-specificity, hindering clinical translation.
• A standardized NRF2 gene signature is needed for reproducible assessment of NRF2 activity.

Purpose of the Study:

• To derive and validate a core NRF2 gene signature for consistent NRF2 activity assessment.
• To investigate the utility of this signature in predicting drug resistance and cancer prognosis.
• To explore NRF2's role in diverse cancer types beyond NRF2-KEAP1 mutations.

Main Methods:

• Analysis of 7 RNA-sequencing datasets to identify core upregulated NRF2 target genes.
• Validation of the NRF2 gene signature using public datasets and gene set enrichment analysis.
• Correlation analysis of NRF2 activity score with drug resistance and patient survival data.

Main Results:

• A robust 14-gene NRF2 signature was defined and validated across multiple datasets.
• The NRF2 activity score correlated with resistance to specific drugs (PX-12, necrosulfonamide) but not others.
• The NRF2 score demonstrated prognostic value for survival in lung adenocarcinoma and other cancer types, including those without NRF2-KEAP1 mutations.

Conclusions:

• The defined NRF2 gene signature is a versatile tool for evaluating NRF2 activity.
• This signature can predict drug resistance and cancer prognosis, offering novel insights into NRF2-driven oncogenesis.
• The findings support the use of this signature for personalized cancer therapy and biomarker development.