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)

    Research output: Contribution to journalArticle

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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

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    Non-Small Cell Lung Carcinoma
    Biomarkers
    Squamous Cell Carcinoma
    Neoplasms
    Cell Line
    Biopsy
    Lung
    Atlases
    Lung Neoplasms
    Adenocarcinoma
    carbonyl reductase (NADPH)
    Genome
    Mutation

    Keywords

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

    Cite this

    MacLeod, A Kenneth ; Acosta-Jimenez, Lourdes ; Coates, Philip J ; McMahon, Michael ; Carey, Frank A. ; Honda, Todashi ; Henderson, Colin J ; Wolf, C Roland. / Aldo-keto reductases are biomarkers of NRF2 activity and are co-ordinately overexpressed in non-small cell lung cancer. In: British Journal of Cancer. 2016 ; Vol. 115, No. 12. pp. 1530-1539.
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    title = "Aldo-keto reductases are biomarkers of NRF2 activity and are co-ordinately overexpressed in non-small cell lung cancer",
    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.",
    keywords = "Lung cancer, biomarkers, stress response, NRF2, aldo-keto reductase",
    author = "MacLeod, {A Kenneth} and Lourdes Acosta-Jimenez and Coates, {Philip J} and Michael McMahon and Carey, {Frank A.} and Todashi Honda and Henderson, {Colin J} and Wolf, {C Roland}",
    note = "This work was supported by Cancer Research UK programme grant C4639/A10822. PJC is supported by project MEYS-NPSI-LO1413. TH is supported by Reta Pharmaceuticals and Stony Brook Foundation.",
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    Aldo-keto reductases are biomarkers of NRF2 activity and are co-ordinately overexpressed in non-small cell lung cancer. / MacLeod, A Kenneth; Acosta-Jimenez, Lourdes; Coates, Philip J ; McMahon, Michael; Carey, Frank A.; Honda, Todashi; Henderson, Colin J; Wolf, C Roland (Lead / Corresponding author).

    In: British Journal of Cancer, Vol. 115, No. 12, 06.12.2016, p. 1530-1539.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Aldo-keto reductases are biomarkers of NRF2 activity and are co-ordinately overexpressed in non-small cell lung cancer

    AU - MacLeod, A Kenneth

    AU - Acosta-Jimenez, Lourdes

    AU - Coates, Philip J

    AU - McMahon, Michael

    AU - Carey, Frank A.

    AU - Honda, Todashi

    AU - Henderson, Colin J

    AU - Wolf, C Roland

    N1 - This work was supported by Cancer Research UK programme grant C4639/A10822. PJC is supported by project MEYS-NPSI-LO1413. TH is supported by Reta Pharmaceuticals and Stony Brook Foundation.

    PY - 2016/12/6

    Y1 - 2016/12/6

    N2 - 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.

    AB - 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.

    KW - Lung cancer

    KW - biomarkers

    KW - stress response

    KW - NRF2

    KW - aldo-keto reductase

    U2 - 10.1038/bjc.2016.363

    DO - 10.1038/bjc.2016.363

    M3 - Article

    VL - 115

    SP - 1530

    EP - 1539

    JO - British Journal of Cancer

    JF - British Journal of Cancer

    SN - 0007-0920

    IS - 12

    ER -