Epigenetic targeting of SLFN11 to overcome ovarian cancer drug-resistances

Development of resistances against cytotoxic treatments is the main cause for therapy failure in ovarian cancer. Among the many mechanisms described, epigenetic silencing of the pro-apoptotic helicase SLFN11 has hardly been investigated so far. Key contributors include methylation of DNA by DNMTs or histones by EZH2, as well as histone deacetylation by HDACs. Although the absence of SLFN11 is considered a marker of drug tolerance in cancer, studies in targeting this helicase in acquired resistant tumors are still lacking. Many patients in the clinic could benefit from these approaches as SLFN11 is silenced in more than 50 % of cancer cell lines.

Here, we investigate whether epigenetic inhibitors can restore SLFN11 expression and thereby sensitize resistant cells to DNA-damaging agents. In qPCR and Western Blot experiments, we show that the HDAC class I inhibitor entinostat increases SLFN11 expression in ovarian cancer cells. This is linked to overcoming resistance to the standard treatment cisplatin and novel PARP-inhibitors, as shown by MTT cell viability assays. We clarify that the induced SLFN11-positive phenotype is related to reduced expression of key DNA-repair proteins, which explains the reversal of resistance. Subsequently, we extend these findings to a newly developed HDAC class I inhibitor, which has already demonstrated superior enzymatic properties compared to entinostat. In conclusion, we show that targeting HDACs to induce SLFN11 activity is a promising way to combat drug resistances, which should be transferred to in vivo studies for a perspective treatment option of patients with still untreatable tumors.