TOPK (T-LAK cell-originated protein kinase) is a novel mitotic kinase and frequently up-regulated in multiple types of cancer, including triple-negative breast cancer (TNBC), but not expressed in normal organs except testis. We previously showed that knockdown of TOPK using siRNAs induced cytokinesis defect in dividing cancer cells with elongated intercellular bridge. In addition, we recently reported that a potent TOPK inhibitor (OTS964) caused the cytokinesis defect and subsequently induced apoptosis of cancer cells in vitro as well as in in vivo xenograft models of human lung cancer. More importantly, liposomal formulation of OTS964 led to complete regression of transplanted tumors without any detectable adverse reactions in mice. Since the TOPK gene is up-regulated in the great majority of TNBCs, we examined therapeutic effect of OTS964 on TNBC cell lines. Western blot analysis revealed that TOPK was highly expressed in all of five TNBC cell lines examined. OTS964 was effective to MDA-MB-231 cells with the IC50 value of 73 nM, and caused cytokinesis defect and apoptosis. Moreover, in MDA-MB-231 xenograft model, oral administration of 75 mg/kg OTS964 for 2 weeks achieved 65% tumor growth inhibitory (TGI) effect at day 15, without any body weight loss. Collectively, our findings imply that targeting TOPK is a very promising therapeutic option for the treatment of TNBC patients who still have very limited treatment modalities.

Citation Format: Jae-Hyun Park, Takashi Miyamoto, Yo Matsuo, Yusuke Nakamura. Therapeutic effects of TOPK inhibitor on triple-negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5415. doi:10.1158/1538-7445.AM2015-5415