Genomic and Epigenomic Signatures in Ovarian Cancer Associated with Resensitization to Platinum Drugs

Abstract

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 (, , 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. Epigenomic targeting may improve therapeutic outcomes in platinum-resistant and recurrent ovarian cancer in part by effects on DNA repair and antitumor immune responses. .

An Effective Epigenetic-PARP Inhibitor Combination Therapy for Breast and Ovarian Cancers Independent of BRCA Mutations

“…The Tukey test for multiple comparisons correction was used to analyze the significance among different groups in biological assays, unless otherwise stated. For in vivo experiments, ANOVA/ Mann-Whitney tests (GraphPad) were used to determine statistical significance, as described (23).…”

“…Based on previous reports demonstrating a functional role for DNMT1 in DNA repair (DDR; refs. 20,21) and our previous studies demonstrating DNMTis ability to resensitize tumors to primary therapies (22,23), we hypothesized that combining a DNMTi with PARPi would sensitize PARPi-resistant ovarian cancer to PARPi therapy, regardless of BRCA status. In support of our hypothesis, it was recently demonstrated that DNMTi-PARPi combination induced PARPi sensitization in leukemia and breast cancer models (24), further suggesting that such a combination approach would impair BRCA-mediated DDR, resulting in cytotoxicity in cells harboring intact or mutant BRCA1/2.…”

Resistance to cis- and carboplatin initiated by epigenetic changes in ovarian cancer patients

“…Resistance/sensitization Genes Cisplatin resistance OXCT1 [18] , GPCR [19] , TET1 [20] , MLH1 [21][22][23] , HOXA10, HOXA11 [21,24] , NAGA [25] , UCHL1 [26] , BCL2L1 [27] , FANCF [28][29][30] Cisplatin sensitization FANCF [31] , NAGA [25] , CCDC69 [32] , UCHL1 [26] Carboplatin Resistance TMEM88 [33] , DOK2 [34,35] , p57(Kip2) [36] , Plk2 [37] , HERV-K [38] , SFRP5 [39] , SLFN11 [40] , ASS1 [41] ASS1: argininosuccinate synthase 1; BCL2L1: BCL2 like 1; CCDC69: coiled-coil domain containing 69; DOK2: docking protein 2; FANCF: fanconi anemia complementation group F; GPCR: protein coupled receptor; HOXA: homeobox A cluster; HERV-K: for HERV-K: human endogenous retrovirus type K; MLH1: mutL homolog 1; NAGA: N-acetylgalactosaminidase; OXCT1: 3-oxoacid CoA-transferase 1; Plk2: polo like kinase 2; SFRP5: secreted frizzled-related protein 5; SLFN11: schlafen family member 11; TET1: tet methylcytosine dioxygenase 1; TMEM88: transmembrane protein 88; UCHL1: ubiquitin C-terminal hydrolase L1 β-catenin independent (non-canonical) pathways. Wnt proteins bind to receptors of the Frizzled and the low-density lipoprotein receptor-related protein families on the cell surface.…”

Targeting Epigenetic Dependencies in Solid Tumors: Evolutionary Landscape Beyond Germ Layers Origin

“…In this context, less than 30% of HGEOC patients survive more than five years [66]. Major causes are identified in diagnosis at advanced stages (III-IV) when the disease has already spread in the abdomen and has acquired or intrinsic resistance to therapy, features that have been linked to CSC and cell plasticity [59,67].…”

“…The DNA methylation status may be interpreted as a tumor fingerprint, resembling the traits of the cell of origin. This could be exploited as a useful clinical tool to (i) identify metastasis of uncertain primary tumor, (ii) to refine the molecular classification of tumors, or (iii) to select patients who could benefit from a specific targeted therapy [64,67,73].…”