J Gynecol Oncol.  2020 Nov;31(6):e93. 10.3802/jgo.2020.31.e93.

High expression of maternal embryonic leucine-zipper kinase (MELK) impacts clinical outcomes in patients with ovarian cancer and its inhibition suppresses ovarian cancer cells growth ex vivo

• Ikeda Y
• Sato S
• Yabuno A
• Shintani D
• Ogasawara A
• Miwa M
• Zewde M
• Miyamoto T
• Fujiwara K
• Nakamura Y
• Hasegawa K

• KMID: 2512058
• DOI: http://doi.org/10.3802/jgo.2020.31.e93

Abstract

Objective
Maternal embryonic leucine zipper kinase (MELK) is receiving an attention as a therapeutic target in various types of cancers. In this study, we aimed to evaluate the prognostic significance of MELK expression in ovarian cancer using clinical samples, and assessed the efficacy of a small molecule MELK inhibitor, OTS167, using patient-derived ovarian cancer cells as well as cell lines.
Methods
Expression levels of MELK in 11 ovarian cancer cell lines were confirmed by western blotting. Inhibitory concentration of OTS167 was determined by colorimetric assay. MELK messenger RNA (mRNA) expression was evaluated in 228 ovarian cancer patients by quantitative polymerase chain reaction. Growth inhibition of OTS167 was also evaluated using freshly-isolated primary ovarian cancer cells including spheroid formation condition.
Results
MELK mRNA expression was significantly higher in ovarian cancer than in normal ovaries (p<0.001), and high MELK mRNA expression was observed in patients with advanced stage, positive ascites cytology and residual tumor size. Patients with high MELK mRNA expression showed shorter progression-free survival (p=0.001). Expression of MELK was also confirmed in 10 of 11 ovarian cancer cell lines tested, and the half maximal inhibitory concentration of MELK inhibitor, OTS167, ranged from 9.3 to 60 nM. Additionally, OTS167 showed significant growth inhibitory effect against patient-derived ovarian cancer cells, regardless of their tumor locations, histologic subtypes and stages.
Conclusions
We demonstrated MELK as both a prognostic marker and a therapeutic target for ovarian cancer using clinical ovarian cancer samples. MELK inhibition by OTS167 may be an effective approach to treat ovarian cancer patients.

Keyword

Ovarian Cancer; MELK; Prognostic Marker; Therapeutic Target