title: Preclinical evaluation of biomarkers associated with antitumor activity of MELK inhibitor.
abstract: 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.
authors.affiliation: OncoTherapy Science, Inc., Kawasaki, Kanagawa, Japan.
authors.forename: Suyoun
authors.initials: S
authors.lastname: Chung
authors.affiliation: OncoTherapy Science, Inc., Kawasaki, Kanagawa, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kijima
authors.affiliation: OncoTherapy Science, Inc., Kawasaki, Kanagawa, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Kudo
authors.affiliation: OncoTherapy Science, Inc., Kawasaki, Kanagawa, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Fujisawa
authors.affiliation: OncoTherapy Science, Inc., Kawasaki, Kanagawa, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Harada
authors.affiliation: OncoTherapy Science, Inc., Kawasaki, Kanagawa, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Taira
authors.affiliation: OncoTherapy Science, Inc., Kawasaki, Kanagawa, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Takamatsu
authors.affiliation: OncoTherapy Science, Inc., Kawasaki, Kanagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyamoto
authors.affiliation: OncoTherapy Science, Inc., Kawasaki, Kanagawa, Japan.
authors.forename: Yo
authors.initials: Y
authors.lastname: Matsuo
authors.affiliation: Department of Medicine and Surgery, The University of Chicago, Chicago, IL, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009287:Naphthyridines / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C585656:1-(6-(3,5-dichloro-4-hydroxyphenyl)-4-((4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)ethanone; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C584411:DEPDC1 protein, human; D020690:GTPase-Activating Proteins; D009287:Naphthyridines; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; C484610:MELK protein, human; D017346:Protein Serine-Threonine Kinases
keywords: MELK; biomarker; kinase inhibitor; molecular pharmacology; xenograft model