title: The combination of alisertib, an investigational Aurora kinase A inhibitor, and docetaxel promotes cell death and reduces tumor growth in preclinical cell models of upper gastrointestinal adenocarcinomas.
abstract: BACKGROUND
  Upper gastrointestinal adenocarcinomas (UGCs) respond poorly to current chemotherapeutic regimes. The authors and others have previously reported frequent Aurora kinase A (AURKA) gene amplification and mRNA and protein overexpression in UGCs. The objective of the current study was to determine the therapeutic potential of alisertib (MLN8237) alone and in combination with docetaxel in UGCs.
  
  
  METHODS
  After treatment with alisertib and/or docetaxel, clonogenic cell survival, cell cycle analyses, Western blot analyses, and tumor xenograft growth assays were carried out to measure cell survival, cell cycle progression, apoptotic protein expression, and tumor xenograft volumes, respectively.
  
  
  RESULTS
  By using the AGS, FLO-1, and OE33 UGC cell lines, which have constitutive AURKA overexpression and variable tumor protein 53 (p53) status, significantly enhanced inhibition of cancer cell survival was observed with alisertib and docetaxel treatment in combination (P < .001), compared with single-agent treatments. Cell cycle analyses, after 48 hours of treatment with alisertib, produced a significant increase in the percentage of polyploidy in UGC cells (P < .01) that was further enhanced by docetaxel (P < .001). In addition, an increase in the percentage of cells in sub-G1-phase observed with alisertib (P < .01) was significantly enhanced with the combination treatment (P < .001). Western blot analysis demonstrated higher induction of cleaved caspase 3 protein expression with the combined treatment compared with single-agent treatments. In addition, FLO-1 and OE33 cell xenograft models demonstrated enhanced antitumor activity for the alisertib and docetaxel combination compared with single-agent treatments (P < .001).
  
  
  CONCLUSIONS
  The current study demonstrated that alisertib combined with docetaxel can mediate a better therapeutic outcome in UGC cell lines.
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
authors.forename: Vikas
authors.initials: V
authors.lastname: Sehdev
authors.forename: Ahmed
authors.initials: A
authors.lastname: Katsha
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ecsedy
authors.forename: Alexander
authors.initials: A
authors.lastname: Zaika
authors.forename: Abbes
authors.initials: A
authors.lastname: Belkhiri
authors.forename: Wael
authors.initials: W
authors.lastname: El-Rifai
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011123:Polyploidy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001381:Azepines; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D043823:Taxoids; D000077143:Docetaxel; C576917:AURKA protein, human; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases