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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Aurora Kinase A
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Aurora Kinases
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Biomarkers
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Cell Cycle / drug effects
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Cell Cycle Proteins / analysis*
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / biosynthesis
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Cell Cycle Proteins / genetics
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Cell Line, Tumor / chemistry
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Cell Line, Tumor / drug effects
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Cell Line, Tumor / enzymology
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Cyclin B / biosynthesis
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Cyclin B / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Drug Resistance, Neoplasm
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Gene Expression Regulation, Neoplastic / drug effects
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Histones / metabolism
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Humans
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Lymphoma, Non-Hodgkin / pathology*
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Microtubule-Associated Proteins / analysis*
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Microtubule-Associated Proteins / antagonists & inhibitors
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Microtubule-Associated Proteins / biosynthesis
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Microtubule-Associated Proteins / genetics
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Neoplasm Proteins / analysis*
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Nuclear Proteins / analysis*
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / genetics
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Phosphorylation / drug effects
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Piperazines / pharmacology*
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Protein Kinase Inhibitors / pharmacology*
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Protein Processing, Post-Translational / drug effects
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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RNA Interference
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RNA, Small Interfering / pharmacology
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Thiazoles / pharmacology*
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Transcription Factors / metabolism
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Xenopus Proteins / metabolism
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Xenopus laevis
Substances
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Antineoplastic Agents
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Biomarkers
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin B
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Cyclin-Dependent Kinase Inhibitor p21
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Histones
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MK-8745
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Microtubule-Associated Proteins
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Neoplasm Proteins
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Nuclear Proteins
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Piperazines
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Protein Kinase Inhibitors
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RNA, Small Interfering
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TACC3 protein, Xenopus
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TPX2 protein, human
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Thiazoles
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Transcription Factors
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Xenopus Proteins
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tozasertib
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AURKA protein, human
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Aurora Kinase A
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Aurora Kinases
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Protein Serine-Threonine Kinases