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: Cyclin-Dependent Kinase Inhibitor p21; 0301 basic medicine; Cell Cycle; Cetuximab; Mice, Nude; Antineoplastic Agents; Apoptosis; Azepines; Irinotecan; 3. Good health; Inhibitory Concentration 50; Mice; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Camptothecin; Female; Drug Screening Assays, Antitumor; Colorectal Neoplasms; Neoplasm Transplantation; Research Paper; Aurora Kinase A; Cell Proliferation

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.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.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.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.