title: A small-molecule inhibitor targeting the mitotic spindle checkpoint impairs the growth of uterine leiomyosarcoma.
abstract: OBJECTIVE
  Uterine leiomyosarcoma (ULMS) is a poorly understood cancer with few effective treatments. This study explores the molecular events involved in ULMS with the goal of developing novel therapeutic strategies.
  
  
  METHODS
  Genome-wide transcriptional profiling, Western blotting, and real-time PCR were used to compare specimens of myometrium, leiomyoma, and leiomyosarcoma. Aurora A kinase was targeted in cell lines derived from metastatic ULMS using siRNA or MK-5108, a highly specific small-molecule inhibitor. An orthotopic model was used to evaluate the ability of MK-5108 to inhibit ULMS growth in vivo.
  
  
  RESULTS
  We found that 26 of 50 gene products most overexpressed in ULMS regulate mitotic centrosome and spindle functions. These include UBE2C, Aurora A and B kinase, TPX2, and Polo-like kinase 1 (PLK1). Targeting Aurora A inhibited proliferation and induced apoptosis in LEIO285, LEIO505, and SK-LMS1, regardless of whether siRNA or MK-5108 was used. In vitro, MK-5108 did not consistently synergize with gemcitabine or docetaxel. Gavage of an orthotopic ULMS model with MK-5108 at 30 or 60 mg/kg decreased the number and size of tumor implants compared with sham-fed controls. Oral MK-5108 also decreased the rate of proliferation, increased intratumoral apoptosis, and increased expression of phospho-histone H3 in ULMS xenografts.
  
  
  CONCLUSIONS
  Our results show that dysregulated centrosome function and spindle assembly are a robust feature of ULMS that can be targeted to slow its growth both in vitro and in vivo. These observations identify novel directions that can be potentially used to improve clinical outcomes for this disease.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Shan
authors.forename: Patricia Y
authors.initials: PY
authors.lastname: Akinfenwa
authors.forename: Kari B
authors.initials: KB
authors.lastname: Savannah
authors.forename: Nonna
authors.initials: N
authors.lastname: Kolomeyevskaya
authors.forename: Rudolfo
authors.initials: R
authors.lastname: Laucirica
authors.forename: Dafydd G
authors.initials: DG
authors.lastname: Thomas
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.forename: Dina C
authors.initials: DC
authors.lastname: Lev
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Anderson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077143:Docetaxel; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007889:Leiomyoma / Q000188:drug therapy / Q000473:pathology; D007890:Leiomyosarcoma / Q000188:drug therapy* / Q000473:pathology; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D009215:Myometrium / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D043823:Taxoids / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: C547876:4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin to 2-yl)methyl) cyclohexanecarboxylic acid; D003509:Cyclohexanecarboxylic Acids; D034741:RNA, Small Interfering; D043823:Taxoids; D013844:Thiazoles; D003841:Deoxycytidine; D000077143:Docetaxel; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D000093542:Gemcitabine