TOPK (T-LAK cell-originated protein kinase) inhibitor exhibits growth suppressive effect on small cell lung cancer

Cancer Sci. 2017 Mar;108(3):488-496. doi: 10.1111/cas.13160.


T-lymphokine-activated killer cell-originated protein kinase (TOPK) plays critical roles in cancer cell proliferation as well as maintenance of cancer stem cells (CSC). Small cell lung cancer (SCLC) has highly aggressive phenotype, reveals early spread to distant sites, and results in dismal prognosis with little effective treatment. In this study, we demonstrate that TOPK expression was highly upregulated in both SCLC cell lines and primary tumors. Similar to siRNA-mediated TOPK knockdown effects, treatment with a potent TOPK inhibitor, OTS514, effectively suppressed growth of SCLC cell lines (IC50 ; 0.4-42.6 nM) and led to their apoptotic cell death. TOPK inhibition caused cell morphologic changes in SCLC cells, elongation of intercellular bridges caused by cytokinesis defects or neuronal protrusions induced by neuronal differentiation in a subset of CSC-like SCLC cells. Treatment with OTS514 suppressed forkhead box protein M1 (FOXM1) activity, which was involved in stemness of CSC. Furthermore, OTS514 treatment reduced CD90-positive SCLC cells and showed higher cytotoxic effect against lung sphere-derived CSC-like SCLC cells. Collectively, our results suggest that targeting TOPK is a promising approach for SCLC therapy.

Keywords: TOPK; Cancer stem cell; kinase inhibitors; molecular target; small cell lung cancer.

MeSH terms

  • Cell Proliferation / drug effects*
  • Cell Proliferation / genetics
  • Forkhead Box Protein M1 / antagonists & inhibitors
  • Humans
  • Lung Neoplasms / pathology*
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Kinases / genetics*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neoplastic Stem Cells / pathology
  • Quinolones / pharmacology*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Small Cell Lung Carcinoma / pathology*
  • Spheroids, Cellular / drug effects
  • Thiophenes / pharmacology*
  • Thy-1 Antigens / metabolism
  • Tumor Cells, Cultured


  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • OTS514
  • Quinolones
  • RNA, Small Interfering
  • Thiophenes
  • Thy-1 Antigens
  • Mitogen-Activated Protein Kinase Kinases
  • PDZ-binding kinase