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


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 (SCCs) 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.
Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK.
A Kenneth
AK
MacLeod
Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK.
Lourdes
L
Acosta-Jimenez
Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK.
Philip J
PJ
Coates
Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK.
Michael
M
McMahon
Department of Pathology and Neuroscience, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
Frank A
FA
Carey
Department of Chemistry and Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA.
Tadashi
T
Honda
Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK.
Colin J
CJ
Henderson
Division of Cancer Research, School of Medicine, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK.
C Roland
CR
Wolf
D000449:Aldehyde Reductase / Q000378:metabolism*; D000074408:Aldo-Keto Reductases; D015415:Biomarkers / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*
D015415:Biomarkers; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase