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

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.

Keywords::

• Aurora
• -A
• MK-8745
• non-Hodgkin lymphoma
• TPX2

Acknowledgements

We thank Merck & Co. for the supply of MK-8745 and VE-465 small-molecule inhibitor and Dr. Wing (John) Chan (Pathology Microbiology, UNMC) for providing human non-Hodgkin lymphoma cell lines.

Grant support: NIH (Nebraska Center for Cellular Signaling 1P20RR018759) and the Eppley Institute for Research in Cancer.

Potential conflict of interest:

Authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.