158P - E-JIB-04: An epigenetic targeted therapy for ovarian cancer with MECOM amplification

Background

One of the major clinical challenges in ovarian cancer (OVCA) is chemotherapy resistance and disease relapse. The existing treatment modalities lack targeted therapeutic strategies for ovarian cancer, which are urgently needed for better patient management. The Cancer Genome Atlas (TCGA) revealed copy number amplification (22%) of a potential oncogene MECOM (MDS1 And EVI1 Complex Locus) in tumor samples of epithelial ovarian cancer patients (n = 489). Recently, epigenetic targeting of amplified oncogenes has emerged as a valuable therapeutic strategy, which intrigued us to investigate whether MECOM, a potential oncogene, may be targeted epigenetically.

Methods

Loss of function study unveiled oncogenic role of MECOM in OVCA cells with MECOM amplification. Screening of selected epigenetic inhibitors was done by cell viability assays. Molecular/cellular changes were analysed at RNA/protein level, and by FACS/confocal imaging. Chromatin level transcriptional regulation of MECOM and KRAS was studied by ChIP–qPCR. The anti-tumorigenic effect of inhibitor was evaluated in in vivo mice model.

Results

RNAi-mediated attenuation of MECOM in OVCA cells reduced their proliferation, impaired colony formation and impeded cellular migration. ChIP-qPCR revealed that MECOM promoted cellular proliferation by transcriptional regulation of KRAS, thus activating its downstream ERK1/2/EGR1/ZEB1 signaling cascade. The anti-tumorigenic effects due to MECOM loss were strikingly phenocopied by histone demethylase inhibitor E-JIB-04, which targeted MECOM expression via altering H3K27 trimethylation at its promoter region. Further, E-JIB-04 pre-treatment reversed the cisplatin resistance in high-MECOM expressing OVCA cells. Administering E-JIB-04 in ovarian cancer xenograft tumors slowed down the tumor growth, concomitant with reducing MECOM expression.

Conclusions

Our findings reveal that MECOM transcriptionally regulates KRAS and is a potential therapeutic target in ovarian cancer. Epigenetic inhibitor E-JIB-04 targets MECOM via modulating histone methylation. Thus, we propose E-JIB-04 as a promising anticancer agent targeting ovarian tumors with MECOM amplification.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.