title: Targeting aurora kinases with danusertib (PHA-739358) inhibits growth of liver metastases from gastroenteropancreatic neuroendocrine tumors in an orthotopic xenograft model.
abstract: OBJECTIVE
  Aurora kinases play a crucial role in cell-cycle control. Uncontrolled expression of aurora kinases causes aneuploidy and tumor growth. As conservative treatment options for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET) are disappointing, aurora kinases may be an interesting target for novel therapeutic strategies.
  
  
  METHODS
  Human GEP-NETs were tested for aurora kinase expression. The efficacy of the new aurora kinase inhibitor danusertib was evaluated in two human GEP-NET cell lines (BON1 and QGP) in vitro and in vivo.
  
  
  RESULTS
  The majority of ten insulinomas and all 33 nonfunctional pancreatic or midgut GEP-NETs expressed aurora A despite a mostly high degree of cell differentiation. Both human GEP-NET cell lines expressed aurora kinase A and B, and high Ser10 phosphorylation of histone H3 revealed increased aurora B activity. Remarkably, danusertib led to cell-cycle arrest and completely inhibited cell proliferation of the GEP-NET cells in vitro. Decreased phosphorylation of histone H3 indicated effective aurora B inhibition. In a subcutaneous murine xenograft model, danusertib significantly reduced tumor growth in vivo compared with controls or mice treated with streptozotocine/5-fluorouracil. As a consequence, decreased levels of tumor marker chromogranin A were found in mouse serum samples. In a newly developed orthotopic model for GEP-NET liver metastases by intrasplenic tumor cell transplantation, dynamic MRI proved significant growth inhibition of BON1- and QGP-derived liver metastases.
  
  
  CONCLUSIONS
  These results show that danusertib may impose a new therapeutic strategy for aurora kinase expressing metastasized GEP-NETs.
authors: I. Medizinische Klinik, Diagnostische und Interventionelle Radiologie, II. Medizinische Klinik, Onkologisches Zentrum, Universitätsklinikum Hamburg-Eppendorf; Labor Lademannbogen, Hamburg, Germany.
authors: Katharina
authors: K
authors: Fraedrich
authors: Jörg
authors: J
authors: Schrader
authors: Harald
authors: H
authors: Ittrich
authors: Gunhild
authors: G
authors: Keller
authors: Artur
authors: A
authors: Gontarewicz
authors: Verena
authors: V
authors: Matzat
authors: Arno
authors: A
authors: Kromminga
authors: Andrea
authors: A
authors: Pace
authors: Jürgen
authors: J
authors: Moll
authors: Michael
authors: M
authors: Bläker
authors: Ansgar W
authors: AW
authors: Lohse
authors: Dieter
authors: D
authors: Hörsch
authors: Tim H
authors: TH
authors: Brümmendorf
authors: Daniel
authors: D
authors: Benten
mesh_terms: D000818:Animals; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001549:Benzamides / Q000008:administration & dosage*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053379:Chromogranin A / Q000097:blood; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006657:Histones / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D051379:Mice; D058990:Molecular Targeted Therapy; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage*; D014183:Transplantation, Heterologous
chemical_list: D001549:Benzamides; D053379:Chromogranin A; D006657:Histones; D011720:Pyrazoles; C576917:AURKA protein, human; 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; C523797:danusertib