The combination of alisertib, an investigational Aurora kinase A inhibitor, and docetaxel promotes cell death and reduces tumor growth in preclinical cell models of upper gastrointestinal adenocarcinomas

• Published in: Cancer 2013-02, Vol.119 (4), p.904-914
• Main Authors: Sehdev, Vikas, Katsha, Ahmed, Ecsedy, Jeffrey, Zaika, Alexander, Belkhiri, Abbes, El‐Rifai, Wael
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - pathology; alisertib; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; apoptosis; Apoptosis - drug effects; Aurora Kinase A; Aurora Kinases; Azepines - administration & dosage; Azepines - pharmacology; Biological and medical sciences; cancer; Cell Cycle Checkpoints - drug effects; Cell Survival - drug effects; docetaxel; esophagus; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gastrointestinal Neoplasms - drug therapy; Gastrointestinal Neoplasms - genetics; Gastrointestinal Neoplasms - pathology; Humans; Medical sciences; Mice; Mice, Nude; mitosis; Polyploidy; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Pyrimidines - administration & dosage; Pyrimidines - pharmacology; stomach; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Taxoids - administration & dosage; Taxoids - pharmacology; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.27801

BACKGROUND: Upper gastrointestinal adenocarcinomas (UGCs) respond poorly to current chemotherapeutic regimes. The authors and others have previously reported frequent Aurora kinase A (AURKA) gene amplification and mRNA and protein overexpression in UGCs. The objective of the current study was to determine the therapeutic potential of alisertib (MLN8237) alone and in combination with docetaxel in UGCs. METHODS: After treatment with alisertib and/or docetaxel, clonogenic cell survival, cell cycle analyses, Western blot analyses, and tumor xenograft growth assays were carried out to measure cell survival, cell cycle progression, apoptotic protein expression, and tumor xenograft volumes, respectively. RESULTS: By using the AGS, FLO‐1, and OE33 UGC cell lines, which have constitutive AURKA overexpression and variable tumor protein 53 (p53) status, significantly enhanced inhibition of cancer cell survival was observed with alisertib and docetaxel treatment in combination (P < .001), compared with single‐agent treatments. Cell cycle analyses, after 48 hours of treatment with alisertib, produced a significant increase in the percentage of polyploidy in UGC cells (P < .01) that was further enhanced by docetaxel (P < .001). In addition, an increase in the percentage of cells in sub‐G1‐phase observed with alisertib (P < .01) was significantly enhanced with the combination treatment (P < .001). Western blot analysis demonstrated higher induction of cleaved caspase 3 protein expression with the combined treatment compared with single‐agent treatments. In addition, FLO‐1 and OE33 cell xenograft models demonstrated enhanced antitumor activity for the alisertib and docetaxel combination compared with single‐agent treatments (P < .001). CONCLUSIONS: The current study demonstrated that alisertib combined with docetaxel can mediate a better therapeutic outcome in UGC cell lines. Cancer 2013. © 2012 American Cancer Society. The combination of alisertib and docetaxel exhibits enhanced anticancer potency in upper gastrointestinal adenocarcinomas both in vitro and in vivo. Therefore, the alisertib and docetaxel combination can mediate a better therapeutic outcome in patients with gastrointestinal cancers.