TARGETING RNA-POLYMERASE I IN BOTH CHEMOSENSITIVE AND CHEMORESISTANT POPULATIONS IN EPITHELIAL OVARIAN CANCER

Purpose: 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 H2AX 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.

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