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

• DOI: 10.18632/oncotarget.10366
• Publication Date: 2016-07-01T18:29:31Z
• Authors: Todd M. Pitts; Erica L. Bradshaw...; Stacey M. Bagby; Stephanie L. Hyatt; Heather M. Selby; Anna Spreafico; John J. Tentler; Kelly McPhillips; Peter J. Klauck; Anna Capasso; Jennifer R. Diamond; S. Lindsey Davis; Aik Choon Tan; John J. Arcaroli; Alicia Purkey; Wells A. Messersmith; Jeffery A. Ecsedy; S. Gail Eckhardt
• Keywords: Aurora kinase

The Aurora kinases are a family of serine/threonine comprised A, B, and C which execute critical steps in mitotic meiotic progression. Alisertib (MLN8237) is an investigational A selective inhibitor that has demonstrated activity against wide variety tumor types vitro vivo, including CRC.CRC cell lines varying sensitivity to alisertib with IC50 values ranging from 0.06 > 5 umol/L. Following exposure we observed decrease pAurora B four CRC lines. We also increase p53 p21 sensitive wildtype line contrast the mutant or resistant addition standard treatments improvement over single agent arms; however, benefit was largely less than additive, but not antagonistic.Forty-seven were exposed IC50s calculated. Twenty-one PDX models treated Tumor Growth Inhibition Index assessed. Additionally, KRAS as combination cetuximab irinotecan, respectively.Alisertib anti-proliferative effects models. Our data suggest therapies colorectal cancer if pursued clinically, will require further investigation patient selection strategies these combinations may facilitate future clinical studies.