2022 World Conference on Lung Cancer (ePosters)-EP08.02-031. NRF2 Pathway Signature Predicts KEAP1/NFE2L2 Mutations and Reveals Alternative Pathway-Activating Mutations in NSCLC

EP08.02-031. NRF2 Pathway Signature Predicts KEAP1/NFE2L2 Mutations and Reveals Alternative Pathway-Activating Mutations in NSCLC

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Researchers from the University of Cologne have developed a transcriptomic signature that can detect alterations in the KEAP1/NFE2L2 pathway in non-small cell lung cancer (NSCLC) patients. The KEAP1/NFE2L2 pathway is associated with aggressive forms of NSCLC that are resistant to current treatments. The signature, which consists of 46 antioxidant genes induced by NRF2 expression, was found to accurately predict KEAP1/NFE2L2 mutations in NSCLC samples. The researchers used RNA and whole exome sequencing data from 971 NSCLC samples to train a logistic regression model, and then validated the model using 348 in-house NSCLC tissue samples. The signature achieved a high area under the curve (AUC) in predicting mutations in KEAP1/NFE2L2, indicating its accuracy.<br /><br />The study also found that the KEAP1/NFE2L2 signature outperformed the mutational status of KEAP1/NFE2L2 in predicting tumor hypoxia. Additionally, lung adenocarcinomas (LUAD) with positive transcriptomic scores but without mutations in KEAP1 or NFE2L2 were significantly enriched for mutations in SMARCA4/BRG1, while false positive lung squamous cell carcinoma (LUSC) samples were enriched for CUL3 mutations. The overlap in upregulated genes between KEAP1/NFE2L2mut, SMARCA4mut, and CUL3mut tumors suggested a shared metabolic reprogramming phenotype.<br /><br />In conclusion, the developed transcriptomic signature accurately predicts functional mutations in KEAP1 and NFE2L2 and demonstrates that most KEAP1 mutations are linked to activation of the anti-oxidant pathway. The signature also identified other mutations, such as SMARCA4/BRG1 and CUL3, that mimic KEAP1/NFE2L2 mutations. This signature has the potential to identify patients for clinical trials targeting NSCLC tumors driven by the KEAP1/NFE2L2 pathway and to guide treatment decisions for these patients.

Asset Subtitle

Christoph Arolt

Meta Tag

Speaker Christoph Arolt

Topic Metastatic Non-small Cell Lung Cancer - Molecular Targeted Treatments

Keywords

transcriptomic signature

KEAP1/NFE2L2 pathway

NSCLC

mutations

RNA sequencing

logistic regression model

tumor hypoxia

LUAD

SMARCA4/BRG1 mutations

CUL3 mutations