Abstract 2164: Mirk/dyrk1B kinase inhibitor reduces the viability of patient-derived ovarian cancer ascites cells and the size of murine tumor xenografts.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Ovarian cancer is one of the most deadly malignancies for women because it typically presents at a late stage when conventional therapies have limited effect. Ovarian cancer often metastasizes by forming peritoneal ascites, consisting of tumor spheroids within a large fluid volume. Others have shown that ascites tumor spheroids are largely quiescent with about 85% in G0/G1, but retain the capacity to re-enter the cell cycle after attachment to the peritoneal cavity walls. Mirk/dyrk1B kinase is most highly expressed when cancer cells are quiescent, and is known to maintain cells in quiescence by destabilizing cyclin D isoforms and by phosphorylating a member of the DREAM complex that enables p130/Rb2 to sequester transcription factors. In earlier studies, Mirk/dyrk1B kinase inhibition or depletion in quiescent adherent cancer cells, either ovarian or pancreatic, allowed cells to escape quiescence, enter cycle prematurely and suffer DNA damage and subsequent apoptosis. No such effects were seen in normal diploid cells in which Mirk/dyrk1B kinase was in low abundance and had low activity, and diploid cells have a normal complement of CDK inhibitors to prevent escape from quiescence. We now show that spheroids from three ovarian cancer cell lines and the Panc1 pancreatic cancer cell line are largely quiescent, and enriched in Mirk/dyrk1B kinase, the quiescence protein p130/Rb2 and the CDK inhibitor p27. Treatment with two novel Mirk/dyrk1B kinase inhibitors led to a decrease in spheroid quiescence markers, and up to a 7-fold decrease in spheroid volume and viable cell numbers. Significantly, Mirk is expressed in patient-derived ovarian cancer ascites spheroids, and ascites treatment with the most potent Mirk/dyrk1B kinase inhibitor led first to an induction of apoptosis markers, then to a disruption of spheroid structure, and finally to a 90% loss in viable tumor cells. This inhibitor, at concentrations that killed patient-derived ovarian cancer ascites spheroid cells in vitro, had no detectable toxicity in mice, not decreasing mouse weight, but reduced the size of Panc1 xenografts up to 3-fold, while increasing the percent of Ki67 positive tumor cells. Both observations were consistent with the model that Mirk/dyrk1B kinase inhibition allowed quiescent tumor cells to enter cycle prematurely where they would die. Citation Format: Xiaobing Deng, Jing Hu, Mary Cunningham, Bertrand Leblond, Thierry Besson, Anne-Sophie Casagrande, Laurent Desire, Eileen A. Friedman. Mirk/dyrk1B kinase inhibitor reduces the viability of patient-derived ovarian cancer ascites cells and the size of murine tumor xenografts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2164. doi:10.1158/1538-7445.AM2013-2164