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: Michelle L Stewart, Pablo Tamayo, Andrew J Wilson, Stephanie Wang, Yun Min Chang, Jong W Kim, Dineo Khabele, Alykhan F Shamji, Stuart L Schreiber
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 14 Pg. 2897-906 (Jul 15 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 25968887 (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)
• Decitabine
• 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