title: Aurora inhibitor MLN8237 in combination with docetaxel enhances apoptosis and anti-tumor activity in mantle cell lymphoma.
abstract: Auroras (A and B) are oncogenic serine/threonine kinases that play key roles in the mitotic phase of the eukaryotic cell cycle. Analysis of the leukemia lymphoma molecular profiling project (LLMPP) database indicates Aurora over-expression correlates with poor prognosis. A tissue microarray (TMA) composed of 20 paired mantle cell lymphoma (MCL) patients demonstrated >75% of patients had high levels Aurora expression. Aurora A and B were also found elevated in 13 aggressive B-NHL cell lines. MLN8237, an Aurora inhibitor induced G2/M arrest with polyploidy and abrogated Aurora A and histone-H3 phosphorylation. MLN8237 inhibited aggressive B-NHL cell proliferation at an IC(50) of 10-50 nM and induced apoptosis in a dose- and time-dependent manner. Low dose combinations of MLN8237+docetaxel enhanced apoptosis by ~3-4-fold in cell culture compared to single agents respectively. A mouse xenograft model of MCL demonstrated that MLN8237 (10 or 30 mg/kg) or docetaxel (10mg/kg) alone had modest anti-tumor activity. However, MLN8237 plus docetaxel demonstrated a statistically significant tumor growth inhibition and enhanced survival compared to single agent therapy. Together, our results suggest that MLN8237 plus docetaxel may represent a novel therapeutic strategy that could be evaluated in early phase trials in relapsed/refractory aggressive B-cell NHL.
authors.affiliation: Arizona Cancer Center, University of Arizona, 1515 N. Campbell Avenue, Tucson, AZ 85724, USA. wenqing@email.arizona.edu
authors.forename: Wenqing
authors.initials: W
authors.lastname: Qi
authors.forename: Laurence S
authors.initials: LS
authors.lastname: Cooke
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Liu
authors.forename: Lisa
authors.initials: L
authors.lastname: Rimsza
authors.forename: Denise J
authors.initials: DJ
authors.lastname: Roe
authors.forename: Ann
authors.initials: A
authors.lastname: Manziolli
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Persky
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Miller
authors.forename: Daruka
authors.initials: D
authors.lastname: Mahadevan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D043823:Taxoids; D000077143:Docetaxel; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases