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...
Main Authors: | , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2020-09-01
|
Series: | Biomolecules |
Subjects: | |
Online Access: | https://www.mdpi.com/2218-273X/10/10/1365 |
id |
doaj-40b3b4326526449895053ad8523b22e5 |
---|---|
record_format |
Article |
spelling |
doaj-40b3b4326526449895053ad8523b22e52020-11-25T03:14:03ZengMDPI AGBiomolecules2218-273X2020-09-01101365136510.3390/biom10101365High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In VitroLaura Torrente0Gunjit Maan1Asma Oumkaltoum Rezig2Jean Quinn3Angus Jackson4Andrea Grilli5Laura Casares6Ying Zhang7Evgeny Kulesskiy8Jani Saarela9Silvio Bicciato10Joanne Edwards11Albena T. Dinkova-Kostova12Laureano de la Vega13Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UKJacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UKUnit of Gastrointestinal Oncology and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1QH, UKUnit of Gastrointestinal Oncology and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1QH, UKJacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UKDepartment of Life Sciences, University of Modena and Reggio Emilia; via G, Campi 287, 41125 Modena, ItalyJacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UKJacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UKInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, Tukholmankatu 8, FI-00290 Helsinki, FinlandInstitute for Molecular Medicine Finland (FIMM), University of Helsinki, Tukholmankatu 8, FI-00290 Helsinki, FinlandDepartment of Life Sciences, University of Modena and Reggio Emilia; via G, Campi 287, 41125 Modena, ItalyUnit of Gastrointestinal Oncology and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1QH, UKJacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UKJacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UKAberrant 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.https://www.mdpi.com/2218-273X/10/10/1365NRF2colorectal cancerdrug screening |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Laura Torrente Gunjit Maan Asma Oumkaltoum Rezig Jean Quinn Angus Jackson Andrea Grilli Laura Casares Ying Zhang Evgeny Kulesskiy Jani Saarela Silvio Bicciato Joanne Edwards Albena T. Dinkova-Kostova Laureano de la Vega |
spellingShingle |
Laura Torrente Gunjit Maan Asma Oumkaltoum Rezig Jean Quinn Angus Jackson Andrea Grilli Laura Casares Ying Zhang Evgeny Kulesskiy Jani Saarela Silvio Bicciato Joanne Edwards Albena T. Dinkova-Kostova Laureano de la Vega High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro Biomolecules NRF2 colorectal cancer drug screening |
author_facet |
Laura Torrente Gunjit Maan Asma Oumkaltoum Rezig Jean Quinn Angus Jackson Andrea Grilli Laura Casares Ying Zhang Evgeny Kulesskiy Jani Saarela Silvio Bicciato Joanne Edwards Albena T. Dinkova-Kostova Laureano de la Vega |
author_sort |
Laura Torrente |
title |
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_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_sort |
high nrf2 levels correlate with poor prognosis in colorectal cancer patients and with sensitivity to the kinase inhibitor at9283 in vitro |
publisher |
MDPI AG |
series |
Biomolecules |
issn |
2218-273X |
publishDate |
2020-09-01 |
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. |
topic |
NRF2 colorectal cancer drug screening |
url |
https://www.mdpi.com/2218-273X/10/10/1365 |
work_keys_str_mv |
AT lauratorrente highnrf2levelscorrelatewithpoorprognosisincolorectalcancerpatientsandwithsensitivitytothekinaseinhibitorat9283invitro AT gunjitmaan highnrf2levelscorrelatewithpoorprognosisincolorectalcancerpatientsandwithsensitivitytothekinaseinhibitorat9283invitro AT asmaoumkaltoumrezig highnrf2levelscorrelatewithpoorprognosisincolorectalcancerpatientsandwithsensitivitytothekinaseinhibitorat9283invitro AT jeanquinn highnrf2levelscorrelatewithpoorprognosisincolorectalcancerpatientsandwithsensitivitytothekinaseinhibitorat9283invitro AT angusjackson highnrf2levelscorrelatewithpoorprognosisincolorectalcancerpatientsandwithsensitivitytothekinaseinhibitorat9283invitro AT andreagrilli highnrf2levelscorrelatewithpoorprognosisincolorectalcancerpatientsandwithsensitivitytothekinaseinhibitorat9283invitro AT lauracasares highnrf2levelscorrelatewithpoorprognosisincolorectalcancerpatientsandwithsensitivitytothekinaseinhibitorat9283invitro AT yingzhang highnrf2levelscorrelatewithpoorprognosisincolorectalcancerpatientsandwithsensitivitytothekinaseinhibitorat9283invitro AT evgenykulesskiy highnrf2levelscorrelatewithpoorprognosisincolorectalcancerpatientsandwithsensitivitytothekinaseinhibitorat9283invitro AT janisaarela highnrf2levelscorrelatewithpoorprognosisincolorectalcancerpatientsandwithsensitivitytothekinaseinhibitorat9283invitro AT silviobicciato highnrf2levelscorrelatewithpoorprognosisincolorectalcancerpatientsandwithsensitivitytothekinaseinhibitorat9283invitro AT joanneedwards highnrf2levelscorrelatewithpoorprognosisincolorectalcancerpatientsandwithsensitivitytothekinaseinhibitorat9283invitro AT albenatdinkovakostova highnrf2levelscorrelatewithpoorprognosisincolorectalcancerpatientsandwithsensitivitytothekinaseinhibitorat9283invitro AT laureanodelavega highnrf2levelscorrelatewithpoorprognosisincolorectalcancerpatientsandwithsensitivitytothekinaseinhibitorat9283invitro |
_version_ |
1724644896134922240 |