American Association for Cancer Research
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Supplemental Figure S3 from KRAS Genomic Status Predicts the Sensitivity of Ovarian Cancer Cells to Decitabine

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posted on 2023-03-30, 23:09 authored by Michelle L. Stewart, Pablo Tamayo, Andrew J. Wilson, Stephanie Wang, Yun Min Chang, Jong W. Kim, Dineo Khabele, Alykhan F. Shamji, Stuart L. Schreiber

A, cell viability after treatment with decitabine (AUC, x-axis) was plotted against DNMT3a or DNMT3b mRNA expression (log2, y-axis). B, western blot analysis was performed after treatment with decitabine (0.5 μM) or DMSO for nine days in eight ovarian cancer cell lines. C, quantification of western blot analysis of DNMT1 after treatment with selumetinib for six days in two KRAS-mutant ovarian cancer cell lines as depicted in the main text.



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. Cancer Res; 75(14); 2897–906. ©2015 AACR.