Targeting RNA-Polymerase I in Both Chemosensitive and Chemoresistant Populations in Epithelial Ovarian Cancer

Robert Cornelison, Zachary C. Dobbin, Ashwini A. Katre, Dae Hoon Jeong, Yinfeng Zhang, Dongquan Chen, Yuliya Petrova, Danielle C. Llaneza, Adam D. Steg, Laura Parsons, David A. Schneider, Charles N. Landen

A hallmark of neoplasia is increased ribosome biogenesis, and targeting this process with RNA polymerase I (Pol I) inhibitors has shown some efficacy.  We examined the contribution and potential targeting of ribosomal machinery in chemotherapy resistant and sensitive models of ovarian cancer.<br /><br />Experimental Design: Pol I machinery expression was examined, and subsequently targeted with the Pol I inhibitor CX-5461, in ovarian cancer cell lines, an immortalized surface epithelial line, and patient derived xenograft (PDX) models with and without chemotherapy.  Effects on viability, Pol I occupancy of rDNA, ribosomal content, and chemosensitivity were examined.<br /><br />Results: In PDX models, ribosomal machinery components were increased in chemotherapy-treated tumors compared to controls. 13 cell lines were sensitive to CX-5461, with IC50s 25nM - 2μM.  Interestingly two chemoresistant lines were 10.5- and 5.5-fold more sensitive than parental lines  . CX-5461 induced DNA damage checkpoint activation and G2/M arrest with increased γH2AX staining.  Chemoresistant cells had 2-4-fold increased rDNA Pol I occupancy and increased rRNA synthesis, despite having slower proliferation rates, while ribosome abundance and translational efficiency were not impaired.  In five PDX models treated with CX-5461, one showed a complete response, one a 55% reduction in tumor volume, and one maintained stable disease for 45 days. <br />   <br />Conclusions: Pol I inhibition with CX-5461 shows high activity in ovarian cancer cell lines and PDX models, with an enhanced effect on chemoresistant cells. Effects occur independent of proliferation rates or dormancy. This represents a novel therapeutic approach that may have preferential activity in chemoresistant populations.