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

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

SN - 0007-0920

VL - 115

SP - 1530

EP - 1539

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 12

ER -