Oncotarget

Research Papers:

Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer

Hiroyuki Inoue, Taigo Kato, Sope Olugbile, Kenji Tamura, Suyoun Chung, Takashi Miyamoto, Yo Matsuo, Ravi Salgia, Yusuke Nakamura _ and Jae-Hyun Park

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Oncotarget. 2016; 7:13621-13633. https://doi.org/10.18632/oncotarget.7297

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Abstract

Hiroyuki Inoue1, Taigo Kato1, Sope Olugbile1, Kenji Tamura1, Suyoun Chung2, Takashi Miyamoto2, Yo Matsuo2, Ravi Salgia1, Yusuke Nakamura1, Jae-Hyun Park1

1Department of Medicine, The University of Chicago, Chicago, IL 60637, USA

2OncoTherapy Science, Inc., Kawasaki, 213-0012, Japan

Correspondence to:

Yusuke Nakamura, e-mail: [email protected]

Keywords: small cell lung cancer, MELK, molecular target, kinase inhibitor, cancer stem cell

Received: December 09, 2015     Accepted: January 29, 2016     Published: February 10, 2016

ABSTRACT

Maternal embryonic leucine zipper kinase (MELK), that plays a critical role in maintenance of cancer stem cells (CSCs), is predominantly expressed in various types of human cancer including small cell lung cancer (SCLC). SCLC usually acquires resistance to anti-cancer drugs and portends dismal prognosis. We have delineated roles of MELK in development/progression of SCLC and examined anti-tumor efficacy of OTS167, a highly potent MELK inhibitor, against SCLC. MELK expression was highly upregulated in both SCLC cell lines and primary tumors. siRNA-mediated MELK knockdown induced significant growth inhibition in SCLC cell lines. Concordantly, treatment with OTS167 exhibited strong cytotoxicity against eleven SCLC cell lines with IC50 of < 10 nM. As similar to siRNA knockdown, OTS167 treatment induced cytokinetic defects with intercellular bridges, and in some cell lines we observed formation of neuronal protrusions accompanied with increase of a neuronal differentiation marker (CD56), indicating that the compound induced differentiation of cancer cells to neuron-like cells. Furthermore, the MELK inhibition decreased its downstream FOXM1 activity and Akt expression in SCLC cells, and led to apoptotic cell death. OTS167 appeared to be more effective to CSCs as measured by the sphere formation assay, thus MELK inhibition might become a promising treatment modality for SCLC.


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