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Torin2 Suppresses Ionizing Radiation-Induced DNA Damage Repair.
Udayakumar, Durga; Pandita, Raj K; Horikoshi, Nobuo; Liu, Yan; Liu, Qingsong; Wong, Kwok-Kin; Hunt, Clayton R; Gray, Nathanael S; Minna, John D; Pandita, Tej K; Westover, Kenneth D.
Afiliación
  • Udayakumar D; a Department of Radiation Oncology and.
  • Pandita RK; c Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, Texas 77030; and.
  • Horikoshi N; a Department of Radiation Oncology and.
  • Liu Y; c Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, Texas 77030; and.
  • Liu Q; a Department of Radiation Oncology and.
  • Wong KK; c Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, Texas 77030; and.
  • Hunt CR; d Center for Thoracic Oncology, Dana Farber Cancer Institute and.
  • Gray NS; e Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
  • Minna JD; d Center for Thoracic Oncology, Dana Farber Cancer Institute and.
  • Pandita TK; a Department of Radiation Oncology and.
  • Westover KD; c Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, Texas 77030; and.
Radiat Res ; 185(5): 527-38, 2016 05.
Article en En | MEDLINE | ID: mdl-27135971
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.
Asunto(s)

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Fármacos Sensibilizantes a Radiaciones / Daño del ADN / Reparación del ADN / Naftiridinas Idioma: En Revista: Radiat Res Año: 2016 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Fármacos Sensibilizantes a Radiaciones / Daño del ADN / Reparación del ADN / Naftiridinas Idioma: En Revista: Radiat Res Año: 2016 Tipo del documento: Article