RNA Polymerase I Inhibition in Ovarian Cancer

Ovarian cancer is the fifth leading cancer killer of women and little progress has been made in achieving better outcomes. A primary reason for its lethality is acquired chemotherapy resistance. We sought to model chemoresistance in patient derived xenografts (PDX) in mice that are treated with standard of care (SOC) chemotherapy. After transcriptomic profiling of treated PDX we identified the ribosome biogenesis system as upregulated in tumors surviving treatment. Our primary hypothesis is that chemoresistant ovarian cancer requires enhanced ribosome RNA transcription to survive chemotherapy, and pharmacologic inhibition of ribogenesis will kill chemoresistant disease. Our results indicated that ovarian cancer is sensitive to RNA polymerase I inhibition with CX-5461, that paclitaxel resistant cells may be hypersensitive to it, and that CX-5461 induces the DNA damage response. During the course of these experiments we observed an unreported effect of CX-5461 treatment. Cytosolic DNA began accumulating ~1 hour after treatment. The cytosolic DNA sensing system activated and led to a type I interferon response. Agonists to the cytosolic DNA sensing system are widely sought after as a possible means of increasing response rates to checkpoint inhibitors.