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Cancer Res DOI:10.1158/0008-5472.CAN-14-2860

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

Publication TypeJournal Article
Year of Publication2015
AuthorsStewart, ML, Tamayo, P, Wilson, AJ, Wang, S, Chang, YMin, Kim, JW, Khabele, D, Shamji, AF, Schreiber, SL
JournalCancer Res
Volume75
Issue14
Pages2897-906
Date Published2015 Jul 15
ISSN1538-7445
KeywordsAnimals, Azacitidine, Biomarkers, Tumor, Cystadenocarcinoma, Serous, Drug Resistance, Neoplasm, Female, Genes, ras, Humans, Mice, Mice, Nude, Mice, Transgenic, Mutation, Ovarian Neoplasms, Prognosis, Tumor Cells, Cultured, Xenograft Model Antitumor Assays
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.

DOI10.1158/0008-5472.CAN-14-2860
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25968887?dopt=Abstract

Alternate JournalCancer Res.
PubMed ID25968887
PubMed Central IDPMC4506246
Grant ListR01 GM074024 / GM / NIGMS NIH HHS / United States
U01 CA176152 / CA / NCI NIH HHS / United States
K08 CA148887 / CA / NCI NIH HHS / United States
K08CA148887 / CA / NCI NIH HHS / United States
U01CA176152 / CA / NCI NIH HHS / United States
R01 CA121941 / CA / NCI NIH HHS / United States