title: Antitumor activity of the aurora a selective kinase inhibitor, alisertib, against preclinical models of colorectal cancer.
abstract: BACKGROUND
  The Aurora kinases are a family of serine/threonine kinases comprised of Aurora A, B, and C which execute critical steps in mitotic and meiotic progression. Alisertib (MLN8237) is an investigational Aurora A selective inhibitor that has demonstrated activity against a wide variety of tumor types in vitro and in vivo, including CRC.
  
  
  RESULTS
  CRC cell lines demonstrated varying sensitivity to alisertib with IC50 values ranging from 0.06 to > 5 umol/L. Following exposure to alisertib we observed a decrease in pAurora A, B and C in four CRC cell lines. We also observed an increase in p53 and p21 in a sensitive p53 wildtype cell line in contrast to the p53 mutant cell line or the resistant cell lines. The addition of alisertib to standard CRC treatments demonstrated improvement over single agent arms; however, the benefit was largely less than additive, but not antagonistic.
  
  
  METHODS
  Forty-seven CRC cell lines were exposed to alisertib and IC50s were calculated. Twenty-one PDX models were treated with alisertib and the Tumor Growth Inhibition Index was assessed. Additionally, 5 KRAS wildtype and mutant PDX models were treated with alisertib as single agent or in combination with cetuximab or irinotecan, respectively.
  
  
  CONCLUSIONS
  Alisertib demonstrated anti-proliferative effects against CRC cell lines and PDX models. Our data suggest that the addition of alisertib to standard therapies in colorectal cancer if pursued clinically, will require further investigation of patient selection strategies and these combinations may facilitate future clinical studies.
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.|University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Pitts
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.|University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.|Takeda California, San Diego, CA, USA.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Bradshaw-Pierce
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Stacey M
authors.initials: SM
authors.lastname: Bagby
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Hyatt
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Selby
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Spreafico
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.|University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Tentler
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: McPhillips
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Klauck
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Capasso
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.|University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Diamond
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.|University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: S Lindsey
authors.initials: SL
authors.lastname: Davis
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.|University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.|University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Arcaroli
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Purkey
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.|University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.affiliation: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA.
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Ecsedy
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.|University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D001381:Azepines / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000068818:Cetuximab / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C117307:KRAS protein, human; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077146:Irinotecan; D064096:Aurora Kinase A; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; D002166:Camptothecin
keywords: aurora kinase a; colorectal cancer