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High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro
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 su...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600603/ https://www.ncbi.nlm.nih.gov/pubmed/32992842 http://dx.doi.org/10.3390/biom10101365 |
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author | Torrente, Laura Maan, Gunjit Oumkaltoum Rezig, Asma 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 |
author_facet | Torrente, Laura Maan, Gunjit Oumkaltoum Rezig, Asma 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 |
author_sort | Torrente, Laura |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7600603 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-76006032020-11-01 High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro Torrente, Laura Maan, Gunjit Oumkaltoum Rezig, Asma 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 Biomolecules Communication 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. MDPI 2020-09-25 /pmc/articles/PMC7600603/ /pubmed/32992842 http://dx.doi.org/10.3390/biom10101365 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Communication Torrente, Laura Maan, Gunjit Oumkaltoum Rezig, Asma 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 High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro |
title | High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro |
title_full | High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro |
title_fullStr | High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro |
title_full_unstemmed | High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro |
title_short | High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro |
title_sort | high nrf2 levels correlate with poor prognosis in colorectal cancer patients and with sensitivity to the kinase inhibitor at9283 in vitro |
topic | Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600603/ https://www.ncbi.nlm.nih.gov/pubmed/32992842 http://dx.doi.org/10.3390/biom10101365 |
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