title: Torin2 Suppresses Ionizing Radiation-Induced DNA Damage Repair.
abstract: Several classes of inhibitors of the mammalian target of rapamycin (mTOR) have been developed based on its central role in sensing growth factor and nutrient levels to regulate cellular metabolism. However, its ATP-binding site closely resembles other phosphatidylinositol 3-kinase-related kinase (PIKK) family members, resulting in reactivity with these targets that may also be therapeutically useful. The ATP-competitive mTOR inhibitor, Torin2, shows biochemical activity against the DNA repair-associated proteins ATM, ATR and DNA-PK, which raises the possibility that Torin2 and related compounds might radiosensitize cancerous tumors. In this study Torin2 was also found to enhance ionizing radiation-induced cell killing in conditions where ATM was dispensable, confirming the requirement for multiple PIKK targets. Moreover, Torin2 did not influence the initial appearance of γ-H2AX foci after irradiation but significantly delayed the disappearance of radiation-induced γ-H2AX foci, indicating a DNA repair defect. Torin2 increased the number of radiation-induced S-phase specific chromosome aberrations and reduced the frequency of radiation-induced CtIP and Rad51 foci formation, suggesting that Torin2 works by blocking homologous recombination (HR)-mediated DNA repair resulting in an S-phase specific DNA repair defect. Accordingly, Torin2 reduced HR-mediated repair of I-Sce1-induced DNA damage and contributed to replication fork stalling. We conclude that radiosensitization of tumor cells by Torin2 is associated with disrupting ATR- and ATM-dependent DNA damage responses. Our findings support the concept of developing combination cancer therapies that incorporate ionizing radiation therapy and Torin2 or compounds with similar properties.
authors.affiliation: a   Department of Radiation Oncology and.|c   Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, Texas 77030; and.
authors.forename: Durga
authors.initials: D
authors.lastname: Udayakumar
authors.affiliation: a   Department of Radiation Oncology and.|c   Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, Texas 77030; and.
authors.forename: Raj K
authors.initials: RK
authors.lastname: Pandita
authors.affiliation: a   Department of Radiation Oncology and.|c   Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, Texas 77030; and.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Horikoshi
authors.affiliation: d   Center for Thoracic Oncology, Dana Farber Cancer Institute and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: e   Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: d   Center for Thoracic Oncology, Dana Farber Cancer Institute and.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: a   Department of Radiation Oncology and.|c   Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, Texas 77030; and.
authors.forename: Clayton R
authors.initials: CR
authors.lastname: Hunt
authors.affiliation: e   Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: b   Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas 75390;
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: a   Department of Radiation Oncology and.|c   Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, Texas 77030; and.
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pandita
authors.affiliation: a   Department of Radiation Oncology and.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Westover
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002869:Chromosome Aberrations / Q000187:drug effects / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects* / Q000528:radiation effects*; D004261:DNA Replication / Q000187:drug effects / Q000528:radiation effects; D016195:G2 Phase / Q000187:drug effects / Q000528:radiation effects; D006657:Histones / Q000378:metabolism; D059765:Homologous Recombination / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007700:Kinetics; D009287:Naphthyridines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects / Q000528:radiation effects
chemical_list: C558529:9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one; C468783:H2AX protein, human; D006657:Histones; D009287:Naphthyridines; D011838:Radiation-Sensitizing Agents