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

// Hiroyuki Inoue 1 , Taigo Kato 1 , Sope Olugbile 1 , Kenji Tamura 1 , Suyoun Chung 2 , Takashi Miyamoto 2 , Yo Matsuo 2 , Ravi Salgia 1 , Yusuke Nakamura 1 , Jae-Hyun Park 1 1 Department of Medicine, The University of Chicago, Chicago, IL 60637, USA 2 OncoTherapy Science, Inc., Kawasaki, 213-0012, Japan Correspondence to: Yusuke Nakamura, e-mail: ynakamura@bsd.uchicago.edu 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 IC 50 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.