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Mol Cancer Ther. 2016 Oct;15(10):2314-2322. Epub 2016 Aug 5.

Barasertib (AZD1152), a Small Molecule Aurora B Inhibitor, Inhibits the Growth of SCLC Cell Lines In Vitro and In Vivo.

Author information

1
Department of Medicine, University of Colorado Cancer Center, Aurora, Colorado.
2
Department of Biostatistics & Informatics, University of Colorado Cancer Center, Aurora, Colorado. Department of Medicine-Pediatrics, University of Colorado Denver-Anschutz Medical Center, Aurora, Colorado.
3
Department of Medicine, University of Colorado Cancer Center, Aurora, Colorado. paul.bunn@ucdenver.edu.

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 IC50 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.

PMID:
27496133
PMCID:
PMC5050114
DOI:
10.1158/1535-7163.MCT-16-0298
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

AstraZeneca provided partial funding for these studies through a sponsored research agreement. The authors have no stock or commercial involvement with AstraZeneca.

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