High NRF2 levels correlate with poor prognosis in colorectal cancer patients and with sensitivity to the kinase inhibitor AT9283 in vitro

Torrente, L. et al. (2020) High NRF2 levels correlate with poor prognosis in colorectal cancer patients and with sensitivity to the kinase inhibitor AT9283 in vitro. Biomolecules, 10(10), 1365. (doi: 10.3390/biom10101365) (PMID:32992842) (PMCID:PMC7600603)

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Abstract

Aberrant hyperactivation of nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2) is a common event in many tumour types and associates with resistance to therapy and poor patient prognosis; however, its relevance in colorectal tumours is not well-established. Measuring the expression of surrogate genes for NRF2 activity in silico, in combination with validation in patients’ samples, we show that the NRF2 pathway is upregulated in colorectal tumours and that high levels of nuclear NRF2 correlate with a poor patient prognosis. These results highlight the need to overcome the protection provided by NRF2 and present an opportunity to selectively kill cancer cells with hyperactive NRF2. Exploiting the CRISPR/Cas9 technology, we generated colorectal cancer cell lines with hyperactive NRF2 and used them to perform a drug screen. We identified AT9283, an Aurora kinase inhibitor, for its selectivity towards killing cancer cells with hyperactive NRF2 as a consequence to either genetic or pharmacological activation. Our results show that hyperactivation of NRF2 in colorectal cancer cells might present a vulnerability that could potentially be therapeutically exploited by using the Aurora kinase inhibitor AT9283.

Item Type:Articles
Additional Information:Funding: This work was supported by the Medical Research Institute of the University of Dundee, Cancer Research UK (C52419/A22869 and C20953/A18644) (L.d.l.V., A.J. and A.T.D.-K.); Ninewells Cancer Campaign (L.T.) and Tenovus Scotland (T18/07) (L.C.).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Quinn, Dr Jean and Edwards, Professor Joanne
Authors: Torrente, L., Maan, G., Oumkaltoum Rezig, A., Quinn, J., Jackson, A., Grilli, A., Casares, L., Zhang, Y., Kulesskiy, E., Saarela, J., Bicciato, S., Edwards, J., Dinkova-Kostova, A. T., and de la Vega, L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Biomolecules
Publisher:MDPI
ISSN:2218-273X
ISSN (Online):2218-273X
Copyright Holders:Copyright © 2020 by the authors
First Published:First published in Biomolecules 10(10):1365
Publisher Policy:Reproduced under a Creative Commons license

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