The kinase inhibitor AT9283 selectively kills colorectal cancer cells with hyperactive NRF2

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

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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

Biomolecules ◽

10.3390/biom10101365 ◽

2020 ◽

Vol 10 (10) ◽

pp. 1365 ◽

Cited By ~ 1

Author(s):

Laura Torrente ◽

Gunjit Maan ◽

Asma Oumkaltoum Rezig ◽

Jean Quinn ◽

Angus Jackson ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Kinase Inhibitor ◽

Aurora Kinase ◽

Related Factor ◽

Aurora Kinase Inhibitor ◽

Poor Patient ◽

Patient Prognosis ◽

Colorectal Tumours

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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Action of a library of O-glycosylation inhibitors on the growth of human colorectal cancer cells in culture

Biochemical Society Transactions ◽

10.1042/bst0330721 ◽

2005 ◽

Vol 33 (4) ◽

pp. 721-723 ◽

Cited By ~ 11

Author(s):

G. Patsos ◽

V. Hebbe-Viton ◽

R. San Martin ◽

C. Paraskeva ◽

T. Gallagher ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Growth ◽

Cancer Cells ◽

Cell Lines ◽

Growth Patterns ◽

Limited Information ◽

Human Colorectal Cancer ◽

Human Colorectal Cancer Cell ◽

Colorectal Cancer Cells ◽

Colorectal Cancer Cell Lines

O-glycosylation is thought to play a significant role in the regulation of cell growth. However, only limited information is available, and few specific and selective inhibitors have been found. We have synthesized a library of O-glycosylation inhibitors based on benzyl-O-N-acetyl-D-galactosamine. These inhibitors were tested with an established series of human colorectal cancer cell lines, which model the adenoma-carcinoma sequence. Cancer cells were incubated with the inhibitors, and examined for cell growth patterns, and cellular and subcellular glycosylation using a range of lectins with confocal microscopy. The specificity of O-glycan inhibition was confirmed for the library, relative to other forms of glycosylation. All inhibitors tested resulted in smaller cell yields. However, a differential effect on O-glycosylation was detected using the lectins showing variation of localization at a subcellular level in the various cell lines. Further differential action of the inhibitor library was observed for apoptosis and on the cell cycle with the cell lines tested. This work demonstrates that O-glycosylation is closely involved in the regulation of cell growth in colorectal cancer cells and that the generation of a library of low-molecular-mass inhibitors offers a valuable means of examining this regulation at the molecular level.

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AMP‐kinase inhibitor dorsomorphin reduces the proliferation and migration behavior of colorectal cancer cells by targeting the AKT/mTOR pathway

IUBMB Life ◽

10.1002/iub.2136 ◽

2019 ◽

Vol 71 (12) ◽

pp. 1929-1936

Author(s):

Sadaf Ghanaatgar‐Kasbi ◽

Forouzan Amerizadeh ◽

Farzad Rahmani ◽

Seyed Mahdi Hassanian ◽

Majid Khazaei ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Kinase Inhibitor ◽

Mtor Pathway ◽

Migration Behavior ◽

Amp Kinase ◽

Colorectal Cancer Cells ◽

And Migration ◽

Proliferation And Migration

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Abstract B30: Colorectal cancer HCT116 cells resistant toward a novel Aurora kinase inhibitor CYC116: Molecular hallmarks of drug resistance and pharmacologic interventions restoring the drug sensitivity

Clinical Cancer Research ◽

10.1158/1078-0432.mechres-b30 ◽

2012 ◽

Vol 18 (10 Supplement) ◽

pp. B30-B30

Author(s):

Madhusudhan Reddy Kollareddy ◽

Daniella Zheleva ◽

Josef Srovnal ◽

Lenka Radova ◽

Petr Dzubak ◽

...

Keyword(s):

Colorectal Cancer ◽

Drug Resistance ◽

Drug Sensitivity ◽

Kinase Inhibitor ◽

Aurora Kinase ◽

Aurora Kinase Inhibitor ◽

Hct116 Cells

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Abstract 2834: Antitumor effect of AGM 130 (5’-OH-5-nitro-Indirubin oxime), a cyclin-dependent kinase inhibitor in colorectal cancer cells

10.1158/1538-7445.am2016-2834 ◽

2016 ◽

Author(s):

Hyun-Jeong Shim ◽

Jun-Eul Hwang ◽

Woo-Kyun Bae ◽

Myung-Sook Park ◽

Hyo-Jeong Yun ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Antitumor Effect ◽

Kinase Inhibitor ◽

Cyclin Dependent Kinase ◽

Cyclin Dependent Kinase Inhibitor ◽

Colorectal Cancer Cells

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An Integrated Bioinformatics Analysis Repurposes an Antihelminthic Drug Niclosamide for Treating HMGA2-Overexpressing Human Colorectal Cancer

Cancers ◽

10.3390/cancers11101482 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1482 ◽

Cited By ~ 6

Author(s):

Leung ◽

Chou ◽

Huang ◽

Yang

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Gene Signature ◽

Cancer Cell Lines ◽

Colorectal Cancer Cell ◽

Sequencing Analysis ◽

Colorectal Cancer Cells ◽

Colorectal Cancer Cell Lines

Aberrant overexpression of high mobility group AT-hook 2 (HMGA2) is frequently found in cancers and HMGA2 has been considered an anticancer therapeutic target. In this study, a pan-cancer genomics survey based on Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) data indicated that HMGA2 was mainly overexpressed in gastrointestinal cancers including colorectal cancer. Intriguingly, HMGA2 overexpression had no prognostic impacts on cancer patients’ overall and disease-free survivals. In addition, HMGA2-overexpressing colorectal cancer cell lines did not display higher susceptibility to a previously identified HMGA2 inhibitor (netroposin). By microarray profiling of HMGA2-driven gene signature and subsequent Connectivity Map (CMap) database mining, we identified that S100 calcium-binding protein A4 (S100A4) may be a druggable vulnerability for HMGA2-overexpressing colorectal cancer. A repurposing S100A4 inhibitor, niclosamide, was found to reverse the HMGA2-driven gene signature both in colorectal cancer cell lines and patients’ tissues. In vitro and in vivo experiments validated that HMGA2-overexpressing colorectal cancer cells were more sensitive to niclosamide. However, inhibition of S100A4 by siRNAs and other inhibitors was not sufficient to exert effects like niclosamide. Further RNA sequencing analysis identified that niclosamide inhibited more cell-cycle-related gene expression in HMGA2-overexpressing colorectal cancer cells, which may explain its selective anticancer effect. Together, our study repurposes an anthelminthic drug niclosamide for treating HMGA2-overexpression colorectal cancer.

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