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 IC50values 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.
authors: Department of Medicine, University of Colorado Cancer Center, Aurora, Colorado.
authors: Barbara A
authors: BA
authors: Helfrich
authors: Department of Medicine, University of Colorado Cancer Center, Aurora, Colorado.
authors: Jihye
authors: J
authors: Kim
authors: Department of Biostatistics & Informatics, University of Colorado Cancer Center, Aurora, Colorado. Department of Medicine-Pediatrics, University of Colorado Denver-Anschutz Medical Center, Aurora, Colorado.
authors: Dexiang
authors: D
authors: Gao
authors: Department of Medicine, University of Colorado Cancer Center, Aurora, Colorado.
authors: Daniel C
authors: DC
authors: Chan
authors: Department of Medicine, University of Colorado Cancer Center, Aurora, Colorado.
authors: Zhiyong
authors: Z
authors: Zhang
authors: Department of Medicine, University of Colorado Cancer Center, Aurora, Colorado.
authors: Aik-Choon
authors: AC
authors: Tan
authors: Department of Medicine, University of Colorado Cancer Center, Aurora, Colorado. paul.bunn@ucdenver.edu.
authors: Paul A
authors: PA
authors: Bunn
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016259:Genes, myc; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010755:Organophosphates / Q000494:pharmacology*; D010766:Phosphorylation; D011123:Polyploidy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D000970:Antineoplastic Agents; D006657:Histones; D010755:Organophosphates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D064107:Aurora Kinase B