title: Aurora A inhibitor (MLN8237) plus vincristine plus rituximab is synthetic lethal and a potential curative therapy in aggressive B-cell non-Hodgkin lymphoma.
abstract: OBJECTIVE
  Aurora A and B are oncogenic serine/threonine kinases that regulate mitosis. Overexpression of Auroras promotes resistance to microtubule-targeted agents. We investigated mechanistic synergy by inhibiting the mitotic spindle apparatus in the presence of MLN8237 [M], an Aurora A inhibitor with either vincristine [MV] or docetaxel [MD] in aggressive B-cell non-Hodgkin lymphoma (B-NHL). The addition of rituximab [R] to MV or MD was evaluated for synthetic lethality.
  
  
  METHODS
  Aggressive B-NHL cell subtypes were evaluated in vitro and in vivo for target modulation and anti-NHL activity with single agents, doublets, and triplets by analyzing cell proliferation, apoptosis, tumor growth, survival, and mechanisms of response/relapse by gene expression profiling with protein validation.
  
  
  RESULTS
  MV is synergistic whereas MD is additive for cell proliferation inhibition in B-NHL cell culture models. Addition of rituximab to MV is superior to MD, but both significantly induce apoptosis compared with doublet therapy. Mouse xenograft models of mantle cell lymphoma showed modest single-agent activity for MLN8237, rituximab, docetaxel, and vincristine with tumor growth inhibition (TGI) of approximately 10% to 15%. Of the doublets, MV caused tumor regression, whereas TGI was observed with MD (approximately 55%-60%) and MR (approximately 25%-50%), respectively. Although MV caused tumor regression, mice relapsed 20 days after stopping therapy. In contrast, MVR was curative, whereas MDR led to TGI of approximately 85%. Proliferation cell nuclear antigen, Aurora B, cyclin B1, cyclin D1, and Bcl-2 proteins of harvested tumors confirmed response and resistance to therapy.
  
  
  CONCLUSIONS
  Addition of rituximab to MV is a novel therapeutic strategy for aggressive B-NHL and warrants clinical trial evaluation.
authors.affiliation: Arizona Cancer Center, the University of Arizona, Tucson, Arizona 85724, USA. dmahadevan@azcc.arizona.edu
authors.forename: Daruka
authors.initials: D
authors.lastname: Mahadevan
authors.forename: Amy
authors.initials: A
authors.lastname: Stejskal
authors.forename: Laurence S
authors.initials: LS
authors.lastname: Cooke
authors.forename: Ann
authors.initials: A
authors.lastname: Manziello
authors.forename: Carla
authors.initials: C
authors.lastname: Morales
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Persky
authors.forename: Richard I
authors.initials: RI
authors.lastname: Fisher
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Miller
authors.forename: Wenqing
authors.initials: W
authors.lastname: Qi
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage*; D034961:Antigens, Nuclear / Q000096:biosynthesis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001381:Azepines / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056744:Cyclin B1 / Q000096:biosynthesis; D019938:Cyclin D1 / Q000096:biosynthesis; D000077143:Docetaxel; D020869:Gene Expression Profiling; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011743:Pyrimidines / Q000008:administration & dosage*; D000069283:Rituximab; D008941:Spindle Apparatus / Q000187:drug effects*; D043823:Taxoids / Q000627:therapeutic use; D014750:Vincristine / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D034961:Antigens, Nuclear; D001381:Azepines; D056744:Cyclin B1; C550258:MLN 8237; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D043823:Taxoids; D019938:Cyclin D1; D000077143:Docetaxel; D000069283:Rituximab; D014750:Vincristine; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576924:Aurkb protein, mouse; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases