Antitumor activity of the aurora a selective kinase inhibitor, alisertib, against preclinical models of colorectal cancer

Oncotarget. 2016 Aug 2;7(31):50290-50301. doi: 10.18632/oncotarget.10366.


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.

Conclusion: 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.

Keywords: aurora kinase a; colorectal cancer.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Aurora Kinase A / antagonists & inhibitors*
  • Azepines / pharmacology*
  • Camptothecin / analogs & derivatives
  • Camptothecin / pharmacology
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation
  • Cetuximab / pharmacology
  • Colorectal Neoplasms / drug therapy*
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Irinotecan
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Pyrimidines / pharmacology*
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Azepines
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • KRAS protein, human
  • MLN 8237
  • Protein Kinase Inhibitors
  • Pyrimidines
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Irinotecan
  • Aurora Kinase A
  • Proto-Oncogene Proteins p21(ras)
  • Cetuximab
  • Camptothecin