Genomic and Epigenomic Signatures in Ovarian Cancer Associated with Re-sensitization to Platinum Drugs

DNA methylation aberrations have been implicated in acquired resistance to platinum drugs in ovarian cancer (OC). In this study, we elucidated an epigenetic signature associated with platinum drug re-sensitization that may offer utility in predicting the outcomes of patients who are co-administered a DNA methyltransferase inhibitror. The OC specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent platinum-resistant OC who received carboplatin plus the DNA methyltransferase inhibitor guadecitabine or a standard of care chemotherapy regimen selected by the treating physician. Tumor biopsies or malignant ascites were collected from patients before treatment (day 1, cycle 1) or after treatment (after 2 cycles) for epigenomic and transcriptomic profiling using the Infinium HumanMethylation450 BeadChip (HM450). We defined 94 gene promoters that were hypomethylated significantly by guadecitabine, with 1659 genes differentially expressed in pre-treatment vs. post-treatment tumors. Pathway analysis revealed that the experimental regimen significantly altered immune re-activation and DNA repair pathways. Progression-free survival correlated with baseline expression levels of 1155 genes involved in 25 networks. In functional investigations in OC cells, engineered upregulation of certain signature genes silenced by promoter methylation (DOK2, miR-293a and others) restored platinum drug sensitivity. Overall, our findings illuminate how inhibiting DNA methylation can sensitize OC cells to platinum drugs, in large part by altering gene expression patterns related to DNA repair and immune activation, with implications for improving the personalized care and survival outcomes of OC patients.

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