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Barasertib (AZD1152), a Small Molecule Aurora B Inhibitor, Inhibits the Growth of SCLC Cell Lines In Vitro and In Vivo.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2016 Oct; Vol. 15 (10), pp. 2314-2322. Date of Electronic Publication: 2016 Aug 05. - Publication Year :
- 2016
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Abstract
- Small-cell lung cancer (SCLC) cells have rapid proliferation, universal Rb inactivation, and high rates of MYC family amplification, making aurora kinase inhibition a natural target. Preclinical studies have demonstrated activity for Aurora A and pan-Aurora inhibitors with some relationship to MYC family expression. A clinical trial showed activity for an Aurora kinase A inhibitor, but no biomarkers were evaluated. We screened a panel of 23 SCLC lines with and without MYC family gene amplification or high MYC family gene expression for growth inhibition by the highly potent, selective aurora kinase B inhibitor barasertib. Nine of the SCLC lines were very sensitive to growth inhibition by barasertib, with IC <subscript>50</subscript> values of <50 nmol/L and >75% growth inhibition at 100 nmol/L. Growth inhibition correlated with cMYC amplification (P = 0.018) and cMYC gene expression (P = 0.026). Sensitive cell lines were also enriched in a published MYC gene signature (P = 0.042). In vivo, barasertib inhibited the growth of xenografts established from an SCLC line that had high cMYC gene expression, no cMYC amplification, and was positive for the core MYC gene signature. Our studies suggest that SCLC tumors with cMYC amplification/high gene expression will frequently respond to Aurora B inhibitors and that clinical studies coupled with predictive biomarkers are indicated. Mol Cancer Ther; 15(10); 2314-22. ©2016 AACR.<br />Competing Interests: AstraZeneca provided partial funding for these studies through a sponsored research agreement. The authors have no stock or commercial involvement with AstraZeneca.<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Animals
Aurora Kinase B antagonists & inhibitors
Cell Line, Tumor
Cell Proliferation drug effects
Cluster Analysis
Disease Models, Animal
Dose-Response Relationship, Drug
Gene Amplification
Gene Expression Profiling
Gene Expression Regulation, Neoplastic drug effects
Genes, myc
Histones metabolism
Humans
Lung Neoplasms drug therapy
Lung Neoplasms metabolism
Lung Neoplasms pathology
Mice
Phosphorylation
Polyploidy
Small Cell Lung Carcinoma drug therapy
Small Cell Lung Carcinoma metabolism
Small Cell Lung Carcinoma pathology
Transcriptome
Tumor Burden drug effects
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Aurora Kinase B metabolism
Organophosphates pharmacology
Protein Kinase Inhibitors pharmacology
Quinazolines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 15
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 27496133
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-16-0298