HOMEPRODUCTSSERVICESCOMPANYCONTACTFAQResearchDictionaryPharmaMobileSign Up FREE or Login

KRAS Genomic Status Predicts the Sensitivity of Ovarian Cancer Cells to Decitabine.

Abstract
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.
AuthorsMichelle L Stewart, Pablo Tamayo, Andrew J Wilson, Stephanie Wang, Yun Min Chang, Jong W Kim, Dineo Khabele, Alykhan F Shamji, Stuart L Schreiber
JournalCancer research (Cancer Res) Vol. 75 Issue 14 Pg. 2897-906 (Jul 15 2015) ISSN: 1538-7445 [Electronic] United States
PMID25968887 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Copyright©2015 American Association for Cancer Research.
Chemical References
  • Biomarkers, Tumor
  • decitabine
  • Azacitidine
Topics
  • Animals
  • Azacitidine (analogs & derivatives, therapeutic use)
  • Biomarkers, Tumor (genetics)
  • Cystadenocarcinoma, Serous (drug therapy, genetics, pathology)
  • Drug Resistance, Neoplasm (genetics)
  • Female
  • Genes, ras
  • Humans
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • Mutation
  • Ovarian Neoplasms (drug therapy, genetics, pathology)
  • Prognosis
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!


Choose Username:
Email:
Password:
Verify Password: