A novel Aurora kinase A inhibitor MK-8745 predicts TPX2 as a therapeutic biomarker in non-Hodgkin lymphoma cell lines

Leuk Lymphoma. 2012 Mar;53(3):462-71. doi: 10.3109/10428194.2011.619018. Epub 2011 Oct 24.

Abstract

Selective small-molecule kinase inhibitors have encouraging clinical efficacy in several malignancies. These agents are still limited to a subset of patients, indicating the need to develop therapeutic biomarkers that influence clinical benefit. In this study, we demonstrate that treatment with MK-8745, a novel Aurora-A specific inhibitor, leads to cell cycle arrest at the G2/M phase with accumulation of tetraploid nuclei followed by cell death in non-Hodgkin lymphoma (NHL) cell lines. The sensitivity of the cell lines to MK-8745 is correlated with the expression level of Aurora-A activator. The siRNA knockdown of Aurora-A activator TPX2 (targeting protein for Xenopus kinase-like protein 2) increased MK-8745 sensitivity in less-MK-8745-sensitive NHL cell lines, whereas overexpression of TPX2 in high-MK-8745-sensitive NHL cell lines increased drug resistance. Our results indicate that TPX2 may serve as a biomarker for identifying subpopulations of patients sensitive to Aurora-A inhibitor treatment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Aurora Kinase A
  • Aurora Kinases
  • Biomarkers
  • Cell Cycle / drug effects
  • Cell Cycle Proteins / analysis*
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / biosynthesis
  • Cell Cycle Proteins / genetics
  • Cell Line, Tumor / chemistry
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / enzymology
  • Cyclin B / biosynthesis
  • Cyclin B / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histones / metabolism
  • Humans
  • Lymphoma, Non-Hodgkin / pathology*
  • Microtubule-Associated Proteins / analysis*
  • Microtubule-Associated Proteins / antagonists & inhibitors
  • Microtubule-Associated Proteins / biosynthesis
  • Microtubule-Associated Proteins / genetics
  • Neoplasm Proteins / analysis*
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Nuclear Proteins / analysis*
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / genetics
  • Phosphorylation / drug effects
  • Piperazines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Processing, Post-Translational / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • RNA Interference
  • RNA, Small Interfering / pharmacology
  • Thiazoles / pharmacology*
  • Transcription Factors / metabolism
  • Xenopus Proteins / metabolism
  • Xenopus laevis

Substances

  • Antineoplastic Agents
  • Biomarkers
  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin B
  • Cyclin-Dependent Kinase Inhibitor p21
  • Histones
  • MK-8745
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • Nuclear Proteins
  • Piperazines
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • TACC3 protein, Xenopus
  • TPX2 protein, human
  • Thiazoles
  • Transcription Factors
  • Xenopus Proteins
  • VX680
  • AURKA protein, human
  • Aurora Kinase A
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases