KRAS genomic status predicts sensitivity to decitabine in an extended assay in ovarian cancer cell lines
Menée sur des lignées cellulaires de cancer de l'ovaire, cette étude suggère l'intérêt d'analyser le statut mutationnel du gène KRAS pour prédire la réponse à un traitement à base de décitabine et navitoclax
Decitabine, a cancer therapeutic that inhibits DNA methylation, has elicited moderate to low response rates in patients with solid tumors. Despite efforts to identify responders based on DNA methylation, a marker for decitabine activity has yet to be determined. Here, we profiled the response of ovarian, melanoma, and breast cancer cell lines to decitabine after treatment for nine days. We found that activation of the RAS/MEK/ERK pathway and DNMT1 expression correlate with decitabine activity. We further showed that KRAS genomic status predicts sensitivity to decitabine in low and high-grade serous ovarian cancer cell lines. We demonstrated that pre-treatment with decitabine decreases activity of MEK inhibitors in KRAS-mutant ovarian cancer cell lines and showed reciprocal regulation of DNMT1 protein level and phosphorylation of MEK and ERK using small-molecule probes targeted to MEK and decitabine, respectively. We observed that decitabine upregulates BNIP3, a pro-apoptotic BCL-2 family member that is regulated by MEK and ERK, and increases activity of navitoclax, a BCL-2 family inhibitor, in KRAS-mutant ovarian cancer cell lines. Finally, we demonstrated that the combination of decitabine and navitoclax greatly decreases tumor burden in a KRAS-mutant ovarian cell line-derived xenograft model. Our results correlate activation of the RAS/MEK/DNMT1 pathway with sensitivity to the DNA methyltransferase inhibitor, decitabine, and implicate KRAS genomic status as a biomarker for sensitivity in ovarian cancer.
Cancer Research , article en libre accès, 2015