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 journalArticle

27 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 1
Externally publishedYes

Fingerprint

Growth Inhibitors
Small Cell Lung Carcinoma
Cell Line
Gene Expression
Growth
Aurora Kinase B
Biomarkers
Aurora Kinases
Aurora Kinase A
Gene Amplification
Heterografts
Genes
Inhibitory Concentration 50
In Vitro Techniques
2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
Clinical Trials
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Barasertib (AZD1152), a small molecule Aurora B inhibitor, inhibits the growth of SCLC cell lines in vitro and in vivo. / Helfrich, Barbara A.; Kim, Jihye; Gao, Dexiang; Chan, Daniel C.; Zhang, Zhiyong; Tan, Aik-Choon; Bunn, Paul A.

In: Molecular Cancer Therapeutics, Vol. 15, No. 10, 01.10.2016, p. 2314-2322.

Research output: Contribution to journalArticle

Helfrich, Barbara A. ; Kim, Jihye ; Gao, Dexiang ; Chan, Daniel C. ; Zhang, Zhiyong ; Tan, Aik-Choon ; Bunn, Paul A. / Barasertib (AZD1152), a small molecule Aurora B inhibitor, inhibits the growth of SCLC cell lines in vitro and in vivo. In: Molecular Cancer Therapeutics. 2016 ; Vol. 15, No. 10. pp. 2314-2322.
@article{ad5250ebe08547718f2309d86e5f0d36,
title = "Barasertib (AZD1152), a small molecule Aurora B inhibitor, inhibits the growth of SCLC cell lines in vitro and in vivo",
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.",
author = "Helfrich, {Barbara A.} and Jihye Kim and Dexiang Gao and Chan, {Daniel C.} and Zhiyong Zhang and Aik-Choon Tan and Bunn, {Paul A.}",
year = "2016",
month = "10",
day = "1",
doi = "10.1158/1535-7163.MCT-16-0298",
language = "English",
volume = "15",
pages = "2314--2322",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "10",

}

TY - JOUR

T1 - Barasertib (AZD1152), a small molecule Aurora B inhibitor, inhibits the growth of SCLC cell lines in vitro and in vivo

AU - Helfrich, Barbara A.

AU - Kim, Jihye

AU - Gao, Dexiang

AU - Chan, Daniel C.

AU - Zhang, Zhiyong

AU - Tan, Aik-Choon

AU - Bunn, Paul A.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84990988111&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84990988111&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-16-0298

DO - 10.1158/1535-7163.MCT-16-0298

M3 - Article

C2 - 27496133

AN - SCOPUS:84990988111

VL - 15

SP - 2314

EP - 2322

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 10

ER -