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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

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NRF2 Pathway Activation and Adjuvant Chemotherapy Benefit in Lung Squamous Cell Carcinoma

David W Cescon1, Desmond She2, Shingo Sakashita3

  • 1Departments of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. Department of Medicine, University of Toronto, Toronto, Canada.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|March 6, 2015
PubMed
Abstract

Insights

Lung squamous cell carcinoma (SCC) with NRF2 pathway activation may not benefit from cisplatin/vinorelbine chemotherapy. This NRF2 activation signature identifies patients who may have reduced benefit from adjuvant chemotherapy.

Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • Genomic profiling reveals NRF2 pathway alterations in approximately one-third of lung squamous cell carcinomas (SCC).
  • These alterations activate oxidative response pathways and may confer resistance to platinum-based chemotherapy.
  • Preclinical data suggest a potential link between NRF2 activation and chemotherapy resistance in SCC.

Purpose of the Study:

  • To evaluate the clinical relevance of NRF2 pathway alterations in SCC.
  • To determine if NRF2 activation predicts benefit from adjuvant chemotherapy in SCC patients.
  • To identify a gene expression signature associated with NRF2 pathway activation.

Main Methods:

  • Logistic regression and significance analysis of microarrays were used to identify genes associated with NRF2 pathway alterations in TCGA SCC data.
  • A 28-gene NRF2 activation signature (NRF2(ACT)) was developed and validated in three independent SCC datasets.
  • Immunohistochemistry and sequencing were performed to correlate gene expression with NRF2/KEAP1 mutational status and protein expression.

Main Results:

  • The NRF2(ACT) signature consistently separated SCC into NRF pathway-activated and wild-type (WT) groups across datasets.
  • NRF2(ACT) was not prognostic on its own.
  • Improved survival with adjuvant cisplatin/vinorelbine was observed in WT patients, while NRF2(ACT) patients showed no benefit (interaction P = 0.15).
  • NRF2(ACT) strongly correlated with NRF2/KEAP1 mutations and high NRF2 protein expression.

Conclusions:

  • A gene expression signature of NRF2 pathway activation is linked to reduced benefit from adjuvant cisplatin/vinorelbine chemotherapy in SCC.
  • Patients with NRF2 pathway-activating somatic alterations may not benefit from this specific adjuvant therapy.
  • The findings highlight the potential of NRF2 pathway status as a predictive biomarker for chemotherapy response in SCC.

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