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

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1365 ◽  
Author(s):  
Laura Torrente ◽  
Gunjit Maan ◽  
Asma Oumkaltoum Rezig ◽  
Jean Quinn ◽  
Angus Jackson ◽  
...  

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.

2019 ◽  
Author(s):  
Laura Torrente ◽  
Gunjit Maan ◽  
Laura Casares ◽  
Angus Jackson ◽  
Tadashi Honda ◽  
...  

ABSTRACTAberrant hyperactivation of NRF2 is a common event in many tumour types and associates with resistance to therapy and poor patient prognosis. The identification of ways to overcome the protection provided by NRF2 and selectively kill cancer cells addicted to NRF2 is a desirable goal. 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 presents a potential vulnerability that could be therapeutically exploited, and further suggest that AT9283, a drug that is currently in clinical trials, holds promise for the treatment of tumours with hyperactive NRF2.HighlightsWe present a new model for NRF2 hyperactivation in colorectal cancer cells.AT9283 selectively kills cancer cells with hyperactive NRF2Both genetic and pharmacological activation of NRF2 sensitise cells to AT9283


PLoS ONE ◽  
2011 ◽  
Vol 6 (8) ◽  
pp. e23485 ◽  
Author(s):  
Chun Hei Antonio Cheung ◽  
Wen-Hsing Lin ◽  
John Tsu-An Hsu ◽  
Tzyh-Chyuan Hour ◽  
Teng-Kuang Yeh ◽  
...  

Cell Cycle ◽  
2019 ◽  
Vol 18 (18) ◽  
pp. 2281-2292
Author(s):  
Muhammad Furqan ◽  
Zille Huma ◽  
Zainab Ashfaq ◽  
Apsra Nasir ◽  
Rahim Ullah ◽  
...  

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