title: 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.
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Stewart
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Pablo
authors.initials: P
authors.lastname: Tamayo
authors.affiliation: Department of Obstetrics and Gynecology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wilson
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Wang
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Yun Min
authors.initials: YM
authors.lastname: Chang
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Jong W
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Obstetrics and Gynecology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Dineo
authors.initials: D
authors.lastname: Khabele
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, Massachusetts. stuart_schreiber@harvard.edu.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D000077209:Decitabine; D001374:Azacitidine