Aldo-keto reductases are biomarkers of NRF2 activity and are co-ordinately overexpressed in non-small cell lung cancer

A Kenneth MacLeod, Lourdes Acosta-Jimenez, Philip J Coates, Michael McMahon, Frank A. Carey, Todashi Honda, Colin J Henderson, C Roland Wolf (Lead / Corresponding author)

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    Abstract

    Background: Although the nuclear factor-erythroid 2-related factor 2 (NRF2) pathway is one of the most frequently dysregulated in cancer, it is not clear whether mutational status is a good predictor of NRF2 activity. Here, we utilise four members of the aldo-keto reductase (AKR) superfamily as biomarkers to address this question.
    Methods: Twenty-three cell lines of diverse origin and NRF2-pathway mutational status were used to determine the relationship between AKR expression and NRF2 activity. AKR expression was evaluated in lung cancer biopsies and Cancer Genome Atlas (TCGA) and Oncomine datasets.
    Results: AKRs were expressed at a high basal level in cell lines carrying mutations in the NRF2 pathway. In non-mutant cell lines, co-ordinate induction of AKRs was consistently observed following activation of NRF2. Immunohistochemical analysis of lung tumour biopsies and interrogation of TCGA data revealed that AKRs are enriched in both squamous cell carcinomas (SCC) and adenocarcinomas that contain somatic alterations in the NRF2 pathway but, in the case of SCC, AKRs were also enriched in most other tumours.
    Conclusions: An AKR biomarker panel can be used to determine NRF2 status in tumours. Hyperactivation of the NRF2 pathway is far more prevalent in lung SCC than previously predicted by genomic analyses.
    Original languageEnglish
    Pages (from-to)1530-1539
    Number of pages10
    JournalBritish Journal of Cancer
    Volume115
    Issue number12
    Early online date8 Nov 2016
    DOIs
    Publication statusPublished - 6 Dec 2016

    Keywords

    • Lung cancer
    • biomarkers
    • stress response
    • NRF2
    • aldo-keto reductase

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