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TTK inhibition radiosensitizes basal-like breast cancer through impaired homologous recombination.
Chandler, Benjamin C; Moubadder, Leah; Ritter, Cassandra L; Liu, Meilan; Cameron, Meleah; Wilder-Romans, Kari; Zhang, Amanda; Pesch, Andrea M; Michmerhuizen, Anna R; Hirsh, Nicole; Androsiglio, Marlie; Ward, Tanner; Olsen, Eric; Niknafs, Yashar S; Merajver, Sofia; Thomas, Dafydd G; Brown, Powel H; Lawrence, Theodore S; Nyati, Shyam; Pierce, Lori J; Chinnaiyan, Arul; Speers, Corey.
Afiliação
  • Chandler BC; Department of Radiation Oncology.
  • Moubadder L; Rogel Cancer Center.
  • Ritter CL; Cancer Biology Program.
  • Liu M; Department of Radiation Oncology.
  • Cameron M; Department of Radiation Oncology.
  • Wilder-Romans K; Department of Radiation Oncology.
  • Zhang A; Department of Radiation Oncology.
  • Pesch AM; Department of Radiation Oncology.
  • Michmerhuizen AR; Department of Radiation Oncology.
  • Hirsh N; Department of Radiation Oncology.
  • Androsiglio M; Department of Radiation Oncology.
  • Ward T; Department of Radiation Oncology.
  • Olsen E; Department of Radiation Oncology.
  • Niknafs YS; Department of Radiation Oncology.
  • Merajver S; Department of Radiation Oncology.
  • Thomas DG; Rogel Cancer Center.
  • Brown PH; Michigan Center for Translation Pathology.
  • Lawrence TS; Rogel Cancer Center.
  • Nyati S; Department of Internal Medicine, and.
  • Pierce LJ; Rogel Cancer Center.
  • Chinnaiyan A; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • Speers C; Department of Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Clin Invest ; 130(2): 958-973, 2020 02 03.
Article em En | MEDLINE | ID: mdl-31961339
Increased rates of locoregional recurrence are observed in patients with basal-like breast cancer (BC) despite the use of radiation therapy (RT); therefore, approaches that result in radiosensitization of basal-like BC are critically needed. Using patients' tumor gene expression data from 4 independent data sets, we correlated gene expression with recurrence to find genes significantly correlated with early recurrence after RT. The highest-ranked gene, TTK, was most highly expressed in basal-like BC across multiple data sets. Inhibition of TTK by both genetic and pharmacologic methods enhanced radiosensitivity in multiple basal-like cell lines. Radiosensitivity was mediated, at least in part, through persistent DNA damage after treatment with TTK inhibition and RT. Inhibition of TTK impaired homologous recombination (HR) and repair efficiency, but not nonhomologous end-joining, and decreased the formation of Rad51 foci. Reintroduction of wild-type TTK rescued both radioresistance and HR repair efficiency after TTK knockdown; however, reintroduction of kinase-dead TTK did not. In vivo, TTK inhibition combined with RT led to a significant decrease in tumor growth in both heterotopic and orthotopic, including patient-derived xenograft, BC models. These data support the rationale for clinical development of TTK inhibition as a radiosensitizing strategy for patients with basal-like BC, and efforts toward this end are currently underway.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tolerância a Radiação / Proteínas Tirosina Quinases / Neoplasias da Mama / Regulação Neoplásica da Expressão Gênica / Proteínas Serina-Treonina Quinases / Proteínas de Ciclo Celular / Bases de Dados de Ácidos Nucleicos / Recombinação Homóloga / Proteínas de Neoplasias Limite: Female / Humans Idioma: En Revista: J Clin Invest Ano de publicação: 2020 Tipo de documento: Article País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tolerância a Radiação / Proteínas Tirosina Quinases / Neoplasias da Mama / Regulação Neoplásica da Expressão Gênica / Proteínas Serina-Treonina Quinases / Proteínas de Ciclo Celular / Bases de Dados de Ácidos Nucleicos / Recombinação Homóloga / Proteínas de Neoplasias Limite: Female / Humans Idioma: En Revista: J Clin Invest Ano de publicação: 2020 Tipo de documento: Article País de publicação: Estados Unidos