Abstract 1251: Significant growth suppressive effects of TOPK and MELK inhibitors in kidney cancer

Abstract

Abstract Kidney cancer is the seventh most common cancer and the tenth most common cause of cancer death for men, and it is the tenth most common cause of cancer for women. The 5-year disease-specific survival has improved from about 50% in 1975-1977 to 65% in 2000-2005, although that of patients at an advanced stage still remains poor with less than 10%; 30% of patients who underwent surgery of localized kidney cancer develop distant metastasis and have limited therapeutic options such as tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors. In addition, the clinical effects of these drugs are limited and patients often discontinue these drugs due to severe side effects including hand-foot syndrome, liver dysfunction and interstitial pneumonia. Therefore, development of more effective therapy for kidney cancer is eagerly expected. T-lymphokine-activated killer cell-originated protein kinase (TOPK) and maternal embryonic leucine zipper kinase (MELK) are promising molecular targets that play critical roles in cancer cell proliferation and maintenance of their stemness. In this study, we investigated growth promotive effect of TOPK and MELK in kidney cancer and found a complex feedback mechanism of these two molecules. Blockade of either of these two kinases effectively caused downregulation of forkhead box protein M1 (FOXM1) activity which is known as an oncogenic transcriptional factor in various types of cancer cell. On the other hand, knockdown and overexpression of FOXM1 caused downregulation and upregulation of both TOPK and MELK mRNA levels, respectively, suggesting that FOXM1 is a critical transcriptional factor for these two molecular targets. Small molecular compound inhibitors against TOPK (OTS514) and MELK (OTS167) effectively suppressed the kidney cancer cell growth and the combination of these two compounds additively induced the very strong growth suppressive effect on kidney cancer cells. Collectively, our results suggest that both TOPK and MELK are promising molecular targets for kidney cancer treatment and that dual blockade of OTS514 and OTS167 should produce synergistic anti-tumor effects with low risk of side effects. Citation Format: Taigo Kato, Hiroyuki Inoue, Seiya Imoto, Yoshinori Tamada, Takashi Miyamoto, Yo Matsuo, Yusuke Nakamura, Jae-Hyun Park. Significant growth suppressive effects of TOPK and MELK inhibitors in kidney cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1251.