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

Laura Torrente Fernandez, Gunjit Maan, Asma Oumkaltoum Rezig, Jean Quinn, Angus Jackson, Andrea Grilli, Laura Casares, Ying Zhang, Evgeny Kulesskiy, Jani Saarela, Silvio Bicciato, Joanne Edwards, Albena Dinkova-Kostova, Laureano de la Vega (Lead / Corresponding author)

Research output: Contribution to journalArticle

5 Downloads (Pure)

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.

Original languageEnglish
Article number1365
Number of pages16
JournalBiomolecules
Volume10
Issue number10
Early online date25 Sep 2020
DOIs
Publication statusPublished - Oct 2020

Keywords

  • NRF2
  • colorectal cancer
  • drug screening

Fingerprint Dive into the research topics of 'High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro'. Together they form a unique fingerprint.

  • Projects

    Cite this

    Torrente Fernandez, 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., & 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, 10(10), [1365]. https://doi.org/10.3390/biom10101365