DNA methylation aberrations have been implicated in acquired resistance to
platinum drugs in
ovarian cancer. In this study, we elucidated an epigenetic signature associated with
platinum drug resensitization that may offer utility in predicting the outcomes of patients who are coadministered
a DNA methyltransferase inhibitor. The
ovarian cancer specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent
platinum-resistant
ovarian cancer 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 1,659 genes differentially expressed in pretreatment versus posttreatment
tumors. Pathway analysis revealed that the experimental regimen significantly altered immune reactivation and DNA repair pathways. Progression-free survival correlated with baseline expression levels of 1,155 genes involved in 25 networks. In functional investigations in
ovarian cancer cells, engineered upregulation of certain signature genes silenced by promoter methylation (DOK2, miR-193a, and others) restored
platinum drug sensitivity. Overall, our findings illuminate how inhibiting DNA methylation can sensitize
ovarian cancer 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
ovarian cancer patients.Significance: Epigenomic targeting may improve therapeutic outcomes in
platinum-resistant and recurrent
ovarian cancer in part by effects on DNA repair and antitumor immune responses.
Cancer Res; 78(3); 631-44. ©2017 AACR.