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KRAS Genomic Status Predicts the Sensitivity of Ovarian Cancer Cells to Decitabine.
Stewart, Michelle L; Tamayo, Pablo; Wilson, Andrew J; Wang, Stephanie; Chang, Yun Min; Kim, Jong W; Khabele, Dineo; Shamji, Alykhan F; Schreiber, Stuart L.
Afiliación
  • Stewart ML; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
  • Tamayo P; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
  • Wilson AJ; Department of Obstetrics and Gynecology, Vanderbilt University, Nashville, Tennessee.
  • Wang S; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
  • Chang YM; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
  • Kim JW; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
  • Khabele D; Department of Obstetrics and Gynecology, Vanderbilt University, Nashville, Tennessee.
  • Shamji AF; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
  • Schreiber SL; The Broad Institute of Harvard and MIT, Cambridge, Massachusetts. stuart_schreiber@harvard.edu.
Cancer Res ; 75(14): 2897-906, 2015 Jul 15.
Article en En | MEDLINE | ID: mdl-25968887
Decitabine, a cancer therapeutic that inhibits DNA methylation, produces variable antitumor response rates in patients with solid tumors that might be leveraged clinically with identification of a predictive biomarker. In this study, we profiled the response of human ovarian, melanoma, and breast cancer cells treated with decitabine, finding that RAS/MEK/ERK pathway activation and DNMT1 expression correlated with cytotoxic activity. Further, we showed that KRAS genomic status predicted decitabine sensitivity in low-grade and high-grade serous ovarian cancer cells. Pretreatment with decitabine decreased the cytotoxic activity of MEK inhibitors in KRAS-mutant ovarian cancer cells, with reciprocal downregulation of DNMT1 and MEK/ERK phosphorylation. In parallel with these responses, decitabine also upregulated the proapoptotic BCL-2 family member BNIP3, which is known to be regulated by MEK and ERK, and heightened the activity of proapoptotic small-molecule navitoclax, a BCL-2 family inhibitor. In a xenograft model of KRAS-mutant ovarian cancer, combining decitabine and navitoclax heightened antitumor activity beyond administration of either compound alone. Our results define the RAS/MEK/DNMT1 pathway as a determinant of sensitivity to DNA methyltransferase inhibition, specifically implicating KRAS status as a biomarker of drug response in ovarian cancer.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Azacitidina / Genes ras / Cistadenocarcinoma Seroso / Resistencia a Antineoplásicos / Mutación Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans Idioma: En Revista: Cancer Res Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Azacitidina / Genes ras / Cistadenocarcinoma Seroso / Resistencia a Antineoplásicos / Mutación Tipo de estudio: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Female / Humans Idioma: En Revista: Cancer Res Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos