mk-8745 and Lymphoma--Non-Hodgkin

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.

Topics: Animals; Antineoplastic Agents; Apoptosis; Aurora Kinase A; Aurora Kinases; Biomarkers; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cyclin B; Cyclin-Dependent Kinase Inhibitor p21; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Histones; Humans; Lymphoma, Non-Hodgkin; Microtubule-Associated Proteins; Neoplasm Proteins; Nuclear Proteins; Phosphorylation; Piperazines; Protein Kinase Inhibitors; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; RNA Interference; RNA, Small Interfering; Thiazoles; Transcription Factors; Xenopus laevis; Xenopus Proteins