title: YU238259 Is a Novel Inhibitor of Homology-Dependent DNA Repair That Exhibits Synthetic Lethality and Radiosensitization in Repair-Deficient Tumors.
abstract: Radiotherapy and DNA-damaging chemotherapy are frequently utilized in the treatment of solid tumors. Innate or acquired resistance to these therapies remains a major clinical challenge in oncology. The development of small molecules that sensitize cancers to established therapies represents an attractive approach to extending survival and quality of life in patients. Here, we demonstrate that YU238259, a member of a novel class of DNA double-strand break repair inhibitors, exhibits potent synthetic lethality in the setting of DNA damage response and DNA repair defects. YU238259 specifically inhibits homology-dependent DNA repair, but not non-homologous end-joining, in cell-based GFP reporter assays. Treatment with YU238259 is not only synergistic with ionizing radiation, etoposide, and PARP inhibition, but this synergism is heightened by BRCA2 deficiency. Further, growth of BRCA2-deficient human tumor xenografts in nude mice is significantly delayed by YU238259 treatment even in the absence of concomitant DNA-damaging therapy. The cytotoxicity of these small molecules in repair-deficient cells results from an accumulation of unresolved DNA double-strand breaks. These findings suggest that YU238259 or related small molecules may have clinical benefit to patients with advanced BRCA2-negative tumors, either as a monotherapy or as an adjuvant to radiotherapy and certain chemotherapies.
  
  
  CONCLUSIONS
  We have identified a novel series of compounds that demonstrate synthetic lethality in DNA repair-deficient cell and animal models and have strong potential for clinical translation.
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut. Department of Genetics, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Stachelek
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Peterson-Roth
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Rafael J
authors.initials: RJ
authors.lastname: Fernandez
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Luke R G
authors.initials: LR
authors.lastname: Pike
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Jack M
authors.initials: JM
authors.lastname: Qian
authors.affiliation: Yale Center for Molecular Discovery, West Haven, Connecticut.
authors.forename: Laura
authors.initials: L
authors.lastname: Abriola
authors.affiliation: Yale Center for Molecular Discovery, West Haven, Connecticut.
authors.forename: Denton
authors.initials: D
authors.lastname: Hoyer
authors.affiliation: Yale Center for Molecular Discovery, West Haven, Connecticut.
authors.forename: William
authors.initials: W
authors.lastname: Hungerford
authors.affiliation: Yale Center for Molecular Discovery, West Haven, Connecticut.
authors.forename: Janie
authors.initials: J
authors.lastname: Merkel
authors.affiliation: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut. Department of Genetics, Yale School of Medicine, New Haven, Connecticut. peter.glazer@yale.edu.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Glazer
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000187:drug effects*; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy; D057166:High-Throughput Screening Assays; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D007364:Intercalating Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents; D054852:Small Molecule Libraries; D013449:Sulfonamides; C000608754:YU238259; D005047:Etoposide