title: Drug-Repositioning Screens Identify Triamterene as a Selective Drug for the Treatment of DNA Mismatch Repair Deficient Cells.
abstract: Purpose:The DNA mismatch repair (MMR) pathway is required for the maintenance of genome stability. Unsurprisingly, mutations in MMR genes occur in a wide range of different cancers. Studies thus far have largely focused on specific tumor types or MMR mutations; however, it is becoming increasingly clear that a therapy targeting MMR deficiency in general would be clinically very beneficial.Experimental Design:Based on a drug-repositioning approach, we screened a large panel of cell lines with various MMR deficiencies from a range of different tumor types with a compound drug library of previously approved drugs. We have identified the potassium-sparing diuretic drug triamterene, as a novel sensitizing agent in MMR-deficient tumor cells,in vitroandin vivoResults:The selective tumor cell cytotoxicity of triamterene occurs through its antifolate activity and depends on the activity of the folate synthesis enzyme thymidylate synthase. Triamterene leads to a thymidylate synthase-dependent differential increase in reactive oxygen species in MMR-deficient cells, ultimately resulting in an increase in DNA double-strand breaks.Conclusions:Conclusively, our data reveal a new drug repurposing and novel therapeutic strategy that has potential for the treatment of MMR deficiency in a range of different tumor types and could significantly improve patient survival.Clin Cancer Res; 23(11); 2880-90. ©2016 AACR.
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
authors.forename: Delphine
authors.initials: D
authors.lastname: Guillotin
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Austin
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
authors.forename: Rumena
authors.initials: R
authors.lastname: Begum
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
authors.forename: Marta O
authors.initials: MO
authors.lastname: Freitas
authors.affiliation: Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
authors.forename: Ashirwad
authors.initials: A
authors.lastname: Merve
authors.affiliation: Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building St James's University Hospital, Beckett St, Leeds, LS9 7TF, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Brend
authors.affiliation: Leeds Institute of Cancer and Pathology, Wellcome Trust Brenner Building St James's University Hospital, Beckett St, Leeds, LS9 7TF, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Short
authors.affiliation: Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, E1 2AT, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marino
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Martin
mesh_terms: D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D053843:DNA Mismatch Repair / Q000235:genetics*; D058492:Drug Repositioning / Q000379:methods; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009386:Neoplastic Syndromes, Hereditary / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014223:Triamterene / Q000494:pharmacology*
chemical_list: D014223:Triamterene