Antitumor activity of the aurora a selective kinase inhibitor, alisertib, against preclinical models of colorectal cancer
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Todd M. Pitts1,3,*, Erica L. Bradshaw-Pierce2,3,5,*, Stacey M. Bagby1, Stephanie L. Hyatt1, Heather M. Selby1, Anna Spreafico1, John J. Tentler1,3, Kelly McPhillips1, Peter J. Klauck1, Anna Capasso1, Jennifer R. Diamond1,3, S. Lindsey Davis1,3, Aik Choon Tan1,3, John J. Arcaroli1,3, Alicia Purkey1, Wells A. Messersmith1,3, Jeffery A. Ecsedy4, S. Gail Eckhardt1,3
1Division of Medical Oncology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
2Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
3University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
4Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
5Takeda California, San Diego, CA, USA
*These authors have contributed equally to this work
Todd M. Pitts, email: Todd.Pitts@ucdenver.edu
Keywords: colorectal cancer, aurora kinase a
Received: January 20, 2016 Accepted: June 17, 2016 Published: July 1, 2016
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.
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