An integrated genomic approach to identify predictive biomarkers of response to the aurora kinase inhibitor PF-03814735
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 trea...
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| Veröffentlicht in: | Molecular cancer therapeutics 2012-03, Vol.11 (3), p.710-719 |
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| creator | Hook, Kenneth E Garza, Scott J Lira, Maruja E Ching, Keith A Lee, Nathan V Cao, Joan Yuan, Jing Ye, Jingjing Ozeck, Mark Shi, Stephanie T Zheng, Xianxian Rejto, Paul A Kan, Julie L C Christensen, James G Pavlicek, Adam |
| description | 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. |
| doi_str_mv | 10.1158/1535-7163.mct-11-0184 |
| format | Article |
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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.</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>DOI: 10.1158/1535-7163.mct-11-0184</identifier><identifier>PMID: 22222631</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; Aurora Kinase A ; Aurora Kinase B ; Aurora Kinases ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - metabolism ; Blotting, Western ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Female ; Gene Expression Profiling ; Genomics - methods ; Heterocyclic Compounds, 3-Ring - pharmacology ; Histones - metabolism ; Humans ; Lung Neoplasms - drug therapy ; Lung Neoplasms - genetics ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Mice ; Mice, Nude ; Phosphorylation - drug effects ; Protein Kinase Inhibitors - pharmacology ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Proto-Oncogene Proteins c-myc - genetics ; Proto-Oncogene Proteins c-myc - metabolism ; Pyrimidines - pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; RNA Interference ; Small Cell Lung Carcinoma - drug therapy ; Small Cell Lung Carcinoma - genetics ; Small Cell Lung Carcinoma - metabolism ; Xenograft Model Antitumor Assays</subject><ispartof>Molecular cancer therapeutics, 2012-03, Vol.11 (3), p.710-719</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c473t-fdda42cb3346cabaa7575299f81d5e456b9f23ce6b031316b5f7104f8aa9602c3</citedby><cites>FETCH-LOGICAL-c473t-fdda42cb3346cabaa7575299f81d5e456b9f23ce6b031316b5f7104f8aa9602c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22222631$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hook, Kenneth E</creatorcontrib><creatorcontrib>Garza, Scott J</creatorcontrib><creatorcontrib>Lira, Maruja E</creatorcontrib><creatorcontrib>Ching, Keith A</creatorcontrib><creatorcontrib>Lee, Nathan V</creatorcontrib><creatorcontrib>Cao, Joan</creatorcontrib><creatorcontrib>Yuan, Jing</creatorcontrib><creatorcontrib>Ye, Jingjing</creatorcontrib><creatorcontrib>Ozeck, Mark</creatorcontrib><creatorcontrib>Shi, Stephanie T</creatorcontrib><creatorcontrib>Zheng, Xianxian</creatorcontrib><creatorcontrib>Rejto, Paul A</creatorcontrib><creatorcontrib>Kan, Julie L C</creatorcontrib><creatorcontrib>Christensen, James G</creatorcontrib><creatorcontrib>Pavlicek, Adam</creatorcontrib><title>An integrated genomic approach to identify predictive biomarkers of response to the aurora kinase inhibitor PF-03814735</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>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.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Aurora Kinase A</subject><subject>Aurora Kinase B</subject><subject>Aurora Kinases</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Blotting, Western</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Female</subject><subject>Gene Expression Profiling</subject><subject>Genomics - methods</subject><subject>Heterocyclic Compounds, 3-Ring - pharmacology</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - pathology</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Phosphorylation - drug effects</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Proto-Oncogene Proteins c-myc - genetics</subject><subject>Proto-Oncogene Proteins c-myc - metabolism</subject><subject>Pyrimidines - pharmacology</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA Interference</subject><subject>Small Cell Lung Carcinoma - drug therapy</subject><subject>Small Cell Lung Carcinoma - genetics</subject><subject>Small Cell Lung Carcinoma - metabolism</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kE1P3DAQhi0E4vsnFPnGKdtMHDvOEa2gRaKCw3K2HGfMumziYHtB--_rdAFfxnr1zIzmIeQHlAsALn8CZ7xoQLDFYFIBUJQg6wNymnNZSA714f__njkhZzH-LTPSVnBMTqr5CQan5ONmpG5M-BJ0wp6-4OgHZ6iepuC1WdPkqetxTM7u6BSwdya5d6Sd84MOrxgi9ZYGjJMfI850WiPV2-CDpq9u1Dl049p1LvlAn-6KkkmoG8YvyJHVm4iXn_WcPN_drpa_i4fHX_fLm4fCZCoVtu91XZmOsVoY3Wnd8IZXbWsl9BxrLrrWVsyg6EoGDETHbQNlbaXWrSgrw87J9X5uvudtizGpwUWDm40e0W-jaqtGSFFLkUm-J03wMQa0agouH7lTUKpZuZp1qlmn-rNc5UjNynPf1eeGbTdg_9315Zj9A9BOfbA</recordid><startdate>201203</startdate><enddate>201203</enddate><creator>Hook, Kenneth E</creator><creator>Garza, Scott J</creator><creator>Lira, Maruja E</creator><creator>Ching, Keith A</creator><creator>Lee, Nathan V</creator><creator>Cao, Joan</creator><creator>Yuan, Jing</creator><creator>Ye, Jingjing</creator><creator>Ozeck, Mark</creator><creator>Shi, Stephanie T</creator><creator>Zheng, Xianxian</creator><creator>Rejto, Paul A</creator><creator>Kan, Julie L C</creator><creator>Christensen, James G</creator><creator>Pavlicek, Adam</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201203</creationdate><title>An integrated genomic approach to identify predictive biomarkers of response to the aurora kinase inhibitor PF-03814735</title><author>Hook, Kenneth E ; Garza, Scott J ; Lira, Maruja E ; Ching, Keith A ; Lee, Nathan V ; Cao, Joan ; Yuan, Jing ; Ye, Jingjing ; Ozeck, Mark ; Shi, Stephanie T ; Zheng, Xianxian ; Rejto, Paul A ; Kan, Julie L C ; Christensen, James G ; Pavlicek, Adam</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c473t-fdda42cb3346cabaa7575299f81d5e456b9f23ce6b031316b5f7104f8aa9602c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Aurora Kinase A</topic><topic>Aurora Kinase B</topic><topic>Aurora Kinases</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Blotting, Western</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Female</topic><topic>Gene Expression Profiling</topic><topic>Genomics - methods</topic><topic>Heterocyclic Compounds, 3-Ring - pharmacology</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - metabolism</topic><topic>Lung Neoplasms - pathology</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Phosphorylation - drug effects</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Proto-Oncogene Proteins c-myc - genetics</topic><topic>Proto-Oncogene Proteins c-myc - metabolism</topic><topic>Pyrimidines - pharmacology</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA Interference</topic><topic>Small Cell Lung Carcinoma - drug therapy</topic><topic>Small Cell Lung Carcinoma - genetics</topic><topic>Small Cell Lung Carcinoma - metabolism</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hook, Kenneth E</creatorcontrib><creatorcontrib>Garza, Scott J</creatorcontrib><creatorcontrib>Lira, Maruja E</creatorcontrib><creatorcontrib>Ching, Keith A</creatorcontrib><creatorcontrib>Lee, Nathan V</creatorcontrib><creatorcontrib>Cao, Joan</creatorcontrib><creatorcontrib>Yuan, Jing</creatorcontrib><creatorcontrib>Ye, Jingjing</creatorcontrib><creatorcontrib>Ozeck, Mark</creatorcontrib><creatorcontrib>Shi, Stephanie T</creatorcontrib><creatorcontrib>Zheng, Xianxian</creatorcontrib><creatorcontrib>Rejto, Paul A</creatorcontrib><creatorcontrib>Kan, Julie L C</creatorcontrib><creatorcontrib>Christensen, James G</creatorcontrib><creatorcontrib>Pavlicek, Adam</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular cancer therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hook, Kenneth E</au><au>Garza, Scott J</au><au>Lira, Maruja E</au><au>Ching, Keith A</au><au>Lee, Nathan V</au><au>Cao, Joan</au><au>Yuan, Jing</au><au>Ye, Jingjing</au><au>Ozeck, Mark</au><au>Shi, Stephanie T</au><au>Zheng, Xianxian</au><au>Rejto, Paul A</au><au>Kan, Julie L C</au><au>Christensen, James G</au><au>Pavlicek, Adam</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>An integrated genomic approach to identify predictive biomarkers of response to the aurora kinase inhibitor PF-03814735</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2012-03</date><risdate>2012</risdate><volume>11</volume><issue>3</issue><spage>710</spage><epage>719</epage><pages>710-719</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><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.</abstract><cop>United States</cop><pmid>22222631</pmid><doi>10.1158/1535-7163.mct-11-0184</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Molecular cancer therapeutics, 2012-03, Vol.11 (3), p.710-719 |
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| source | MEDLINE; American Association for Cancer Research; Free E-Journal (出版社公開部分のみ） |
| subjects | Animals Antineoplastic Agents - pharmacology Aurora Kinase A Aurora Kinase B Aurora Kinases Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Blotting, Western Cell Line, Tumor Cell Proliferation - drug effects Female Gene Expression Profiling Genomics - methods Heterocyclic Compounds, 3-Ring - pharmacology Histones - metabolism Humans Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - metabolism Lung Neoplasms - pathology Mice Mice, Nude Phosphorylation - drug effects Protein Kinase Inhibitors - pharmacology Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Proto-Oncogene Proteins c-myc - genetics Proto-Oncogene Proteins c-myc - metabolism Pyrimidines - pharmacology Reverse Transcriptase Polymerase Chain Reaction RNA Interference Small Cell Lung Carcinoma - drug therapy Small Cell Lung Carcinoma - genetics Small Cell Lung Carcinoma - metabolism Xenograft Model Antitumor Assays |
| title | An integrated genomic approach to identify predictive biomarkers of response to the aurora kinase inhibitor PF-03814735 |
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