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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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.
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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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