Abstract
PF-03814735 is a novel, reversible inhibitor of Aurora kinases A and B that finished a phase I clinical trial for the treatment of advanced solid tumors. To find predictive biomarkers of drug sensitivity, we screened a diverse panel of 87 cancer cell lines for growth inhibition upon PF-03814735 treatment. Small cell lung cancer (SCLC) and, to a lesser extent, colon cancer lines were very sensitive to PF-03814735. The status of the Myc gene family and retinoblastoma pathway members significantly correlated with the efficacy of PF-03814735. Whereas RB1 inactivation, intact CDKN2A/p16, and normal CCND1/Cyclin D1 status are hallmarks of SCLC, activation or amplification of any of the three Myc genes (MYC, MYCL1, and MYCN) clearly differentiated cell line sensitivity within the SCLC panel. By contrast, we found that expression of Aurora A and B were weak predictors of response. We observed a decrease in histone H3 phosphorylation and polyploidization of sensitive lines, consistent with the phenotype of Aurora B inhibition. In vivo experiments with two SCLC xenograft models confirmed the sensitivity of Myc gene-driven models to PF-03814735 and a possible schedule dependence of MYC/c-Myc-driven tumors. Altogether our results suggest that SCLC and other malignancies driven by the Myc family genes may be suitable indications for treatment by Aurora B kinase inhibitors.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Aurora Kinase A
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Aurora Kinase B
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Aurora Kinases
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Biomarkers, Tumor / genetics*
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Biomarkers, Tumor / metabolism
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Blotting, Western
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Female
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Gene Expression Profiling
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Genomics / methods
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Heterocyclic Compounds, 3-Ring / pharmacology*
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Histones / metabolism
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Mice
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Mice, Nude
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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Pyrimidines / pharmacology*
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Small Cell Lung Carcinoma / drug therapy
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Small Cell Lung Carcinoma / genetics
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Small Cell Lung Carcinoma / metabolism
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Biomarkers, Tumor
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Heterocyclic Compounds, 3-Ring
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Histones
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N-(2-(6-(4-cyclobutylamino-5-trifluoromethylpyrimidine-2-ylamino)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl)-2-oxo-ethyl)acetamide
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-myc
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Pyrimidines
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AURKB protein, human
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Aurka protein, mouse
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Aurkb protein, mouse
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Aurora Kinase A
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Aurora Kinase B
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Aurora Kinases
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Protein Serine-Threonine Kinases