Preclinical evaluation of biomarkers associated with antitumor activity of MELK inhibitor
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Suyoun Chung1, Kyoko Kijima1, Aiko Kudo1, Yoshiko Fujisawa1, Yosuke Harada1, Akiko Taira1, Naofumi Takamatsu1, Takashi Miyamoto1, Yo Matsuo1 and Yusuke Nakamura2
1 OncoTherapy Science, Inc., Kawasaki, Kanagawa, Japan
2 Department of Medicine and Surgery, The University of Chicago, Chicago, IL, USA
Yusuke Nakamura, email:
Keywords: MELK, xenograft model, kinase inhibitor, molecular pharmacology, biomarker
Received: December 22, 2015 Accepted: February 08, 2016 Published: February 24, 2016
MELK is upregulated in various types of human cancer and is known to be associated with cancer progression, maintenance of stemness, and poor prognosis. OTS167, a MELK kinase inhibitor, shows potent growth-suppressive effect on human tumors in a xenograft model, but the detailed mode of action has not been fully elucidated. In this study, we demonstrate the molecular mechanism of action of MELK inhibitor OTS167 in a preclinical model. OTS167-treated cells caused morphological transformation, induced the differentiation markers, and reduced stem-cell marker expression. Furthermore, we identified DEPDC1, known as an oncogene, as an additional downstream molecule of the MELK signaling pathway. MELK enhanced DEPDC1 phosphorylation and its stability. The expression of MELK and downstream molecules was decreased in OTS167-treated xenograft tumor tissues, which revealed central necrosis and significant growth suppression. Our data should further shed light on the mechanism of action how OTS167 suppresses tumor growth through the inhibition of the MELK signaling pathway and suggest the possibility of biomarkers for the assessment of clinical efficacy.
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