Barasertib (AZD1152), a small molecule Aurora B inhibitor, inhibits the growth of SCLC cell lines in vitro and in vivo

Barbara A. Helfrich, Jihye Kim, Dexiang Gao, Daniel C. Chan, Zhiyong Zhang, Aik Choon Tan, Paul A. Bunn

Research output: Contribution to journalArticlepeer-review

77 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2314-2322
Number of pages9
JournalMolecular cancer therapeutics
Volume15
Issue number10
DOIs
Publication statusPublished - 2016 Oct

Bibliographical note

Funding Information:
The authors thank the University of Colorado Cancer Center Flow Cytometry Shared Resources Core. These studies were supported by a NCI SPOREP50-CA058187 (to P.A. Bunn) and a research contract from AstraZeneca (to P.A. Bunn). The Cancer Center Shared Resources are supported by NIH grant 2-P30-CA46934. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Publisher Copyright:
©2016 AACR.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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