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Updated: Jul 22, 2025

Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
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Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer

Published on: September 8, 2023

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KEAP1/NFE2L2 Pathway Signature Outperforms KEAP1/NFE2L2 Mutation Status and Reveals Alternative Pathway-Activating

Christoph Arolt1, Margaret Dugan2, Robert Wild2

  • 1Institute of Pathology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer
|July 20, 2023
PubMed
Abstract

Insights

A new K1N2-score accurately identifies tumors with an activated KEAP1/NFE2L2 (NRF2) pathway in non-small cell lung cancer (NSCLC). This signature is a promising tool for selecting patients for targeted therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • The KEAP1/NFE2L2 (NRF2) pathway is crucial in non-small cell lung cancer (NSCLC), driving glutamine dependence and aggressive tumor phenotypes.
  • Activation of this pathway presents a potential therapeutic target in NSCLC treatment.

Purpose of the Study:

  • To develop and validate a transcriptomic signature for identifying KEAP1/NFE2L2-activated tumors in NSCLC.
  • To assess the signature's ability to predict pathway activation and patient survival.

Main Methods:

  • A 46-gene expression signature (K1N2-score) was developed using 971 NSCLC samples to predict KEAP1/NFE2L2 mutations.
  • The signature was validated in an independent cohort of 348 NSCLC samples using NanoString expression analysis.

Main Results:

  • The K1N2-score accurately predicted KEAP1/NFE2L2 mutations (AUC: 89.5%, sensitivity: 90.2%) across different histologies.
  • The K1N2-score demonstrated superior predictive value for patient survival compared to KEAP1/NFE2L2 mutational status.
  • SMARCA4/BRG1 and CUL3 mutations were identified as alternative genomic drivers mimicking KEAP1/NFE2L2 activation.

Conclusions:

  • The K1N2-score effectively identifies KEAP1/NFE2L2-activated NSCLC, including cases with alternative genomic drivers.
  • This signature holds potential for selecting patients with a constitutively active KEAP1/NFE2L2 pathway for targeted therapies.
Keywords:
KEAP1Lung cancerNRF2NSCLCTranscriptomics

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