High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro

Show full item record



Permalink

http://hdl.handle.net/10138/321957

Citation

Torrente , L , Maan , G , Rezig , A O , Quinn , J , Jackson , A , Grilli , A , Casares , L , Zhang , Y , Kulesskiy , E , Saarela , J , Bicciato , S , Edwards , J , Dinkova-Kostova , A T & de la Vega , L 2020 , ' High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro ' , Biomolecules , vol. 10 , no. 10 , 1365 . https://doi.org/10.3390/biom10101365

Title: High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro
Author: Torrente, Laura; Maan, Gunjit; Rezig, Asma Oumkaltoum; Quinn, Jean; Jackson, Angus; Grilli, Andrea; Casares, Laura; Zhang, Ying; Kulesskiy, Evgeny; Saarela, Jani; Bicciato, Silvio; Edwards, Joanne; Dinkova-Kostova, Albena T.; de la Vega, Laureano
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
Date: 2020-10
Language: eng
Number of pages: 16
Belongs to series: Biomolecules
ISSN: 2218-273X
URI: http://hdl.handle.net/10138/321957
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.
Subject: NRF2
colorectal cancer
drug screening
SMALL-MOLECULE INHIBITOR
POTENT AURORA KINASE
PHASE-I
NEGATIVE REGULATION
LUNG-CARCINOMA
TUMOR-GROWTH
KEAP1
RESISTANCE
PATHWAY
EXPRESSION
3111 Biomedicine
1182 Biochemistry, cell and molecular biology
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
biomolecules_10_01365_1.pdf 2.738Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record