title: 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.
authors: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696, USA.
authors: Aparajita
authors: A
authors: Chowdhury
authors: Sanjib
authors: S
authors: Chowdhury
authors: Ming Ying
authors: MY
authors: Tsai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A; D064127:Aurora Kinases; D015415:Biomarkers; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D019926:Cyclin B / Q000096:biosynthesis / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D029867:Xenopus Proteins / Q000378:metabolism; D014982:Xenopus laevis; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D000970:Antineoplastic Agents; D064096:Aurora Kinase A; D064127:Aurora Kinases; D015415:Biomarkers; D018797:Cell Cycle Proteins; D019926:Cyclin B; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D013844:Thiazoles; D014157:Transcription Factors; D029867:Xenopus Proteins; C493956:CDKN1A protein, human; C574019:MK-8745; C474872:TACC3 protein, Xenopus; C122167:TPX2 protein, human; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C576917:AURKA protein, human