title: G-quadruplex DNA as a molecular target for induced synthetic lethality in cancer cells.
abstract: Synthetic lethality is a genetic concept in which cell death is induced by the combination of mutations in two sensitive genes, while mutation of either gene alone is not sufficient to affect cell survival. Synthetic lethality can also be achieved "chemically" by combination of drug-like molecules targeting distinct but cooperative pathways. Previously, we reported that the small molecule pyridostatin (PDS) stabilizes G-quadruplexes (G4s) in cells and elicits a DNA damage response by causing the formation of DNA double strand breaks (DSB). Cell death mediated by ligand-induced G4 stabilization can be potentiated in cells deficient in DNA damage repair genes. Here, we demonstrate that PDS acts synergistically both with NU7441, an inhibitor of the DNA-PK kinase crucial for nonhomologous end joining repair of DNA DSBs, and BRCA2-deficient cells that are genetically impaired in homologous recombination-mediated DSB repair. G4 targeting ligands have potential as cancer therapeutic agents, acting synergistically with inhibition or mutation of the DNA damage repair machinery.
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, United Kingdom.
authors.forename: Keith I E
authors.initials: KI
authors.lastname: McLuckie
authors.forename: Marco
authors.initials: M
authors.lastname: Di Antonio
authors.forename: Heather
authors.initials: H
authors.lastname: Zecchini
authors.forename: Jian
authors.initials: J
authors.lastname: Xian
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.forename: Ben-Fillippo
authors.initials: BF
authors.lastname: Krippendorff
authors.forename: David
authors.initials: D
authors.lastname: Tannahill
authors.forename: Christopher
authors.initials: C
authors.lastname: Lowe
authors.forename: Shankar
authors.initials: S
authors.lastname: Balasubramanian
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D024682:BRCA2 Protein / Q000172:deficiency / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000737:chemistry / Q000494:pharmacology; D053960:DNA Breaks; D004273:DNA, Neoplasm / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D054856:G-Quadruplexes; D006801:Humans; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D010848:Picolinic Acids / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C499693:8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one; D000634:Aminoquinolines; D000970:Antineoplastic Agents; D024682:BRCA2 Protein; D002867:Chromones; D004273:DNA, Neoplasm; D009025:Morpholines; D010848:Picolinic Acids; C567962:pyridostatin