Inhibition of the ERCC1–XPF structure-specific endonuclease to overcome cancer chemoresistance |
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| Institution: | 1. MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK;2. Centre for Translational and Chemical Biology, School of Biological Sciences, University of Edinburgh, Michael Swann Building, The King''s Buildings, Mayfield Road, Edinburgh EH9 3JR, UK;3. Centre for Therapeutics Discovery, MRC Technology, 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, UK;1. Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA;2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA;1. Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA;2. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA;3. Laboratory of Genome Maintenance, Rockefeller University, New York, NY 10065, USA;4. Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA;1. Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK;2. Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK;3. Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK;4. Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham NG51PB, UK;5. NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA;6. Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG51PB, UK;7. School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham NG11 8NS, UK;8. Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224-6825, USA |
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| Abstract: | ERCC1–XPF is a structure-specific endonuclease that is required for the repair of DNA lesions, generated by the widely used platinum-containing cancer chemotherapeutics such as cisplatin, through the Nucleotide Excision Repair and Interstrand Crosslink Repair pathways. Based on mouse xenograft experiments, where ERCC1-deficient melanomas were cured by cisplatin therapy, we proposed that inhibition of ERCC1–XPF could enhance the effectiveness of platinum-based chemotherapy. Here we report the identification and properties of inhibitors against two key targets on ERCC1–XPF. By targeting the ERCC1–XPF interaction domain we proposed that inhibition would disrupt the ERCC1–XPF heterodimer resulting in destabilisation of both proteins. Using in silico screening, we identified an inhibitor that bound to ERCC1–XPF in a biophysical assay, reduced the level of ERCC1–XPF complexes in ovarian cancer cells, inhibited Nucleotide Excision Repair and sensitised melanoma cells to cisplatin. We also utilised high throughput and in silico screening to identify the first reported inhibitors of the other key target, the XPF endonuclease domain. We demonstrate that two of these compounds display specificity in vitro for ERCC1–XPF over two other endonucleases, bind to ERCC1–XPF, inhibit Nucleotide Excision Repair in two independent assays and specifically sensitise Nucleotide Excision Repair-proficient, but not Nucleotide Excision Repair-deficient human and mouse cells to cisplatin. |
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| Keywords: | Nucleotide Excision Repair Interstrand Crosslink Repair DNA repair inhibitor ERCC1–XPF FANCQ Melanoma Ovarian cancer |
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