The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models
The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC...
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| Veröffentlicht in: | Oncogene 2016-02, Vol.35 (7), p.833-845 |
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| creator | Garcia, P L Miller, A L Kreitzburg, K M Council, L N Gamblin, T L Christein, J D Heslin, M J Arnoletti, J P Richardson, J H Chen, D Hanna, C A Cramer, S L Yang, E S Qi, J Bradner, J E Yoon, K J |
| description | The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT–PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (
P |
| doi_str_mv | 10.1038/onc.2015.126 |
| format | Article |
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P
<0.05), each of which harbors a KRAS mutation; but induced no consistent change in expression of c-Myc protein. Expression profiling identified CDC25B, a regulator of cell cycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (
P
<0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2015.126</identifier><identifier>PMID: 25961927</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/51 ; 14/63 ; 45/77 ; 631/67/1059/602 ; 64/60 ; 82/29 ; Adenocarcinoma ; Animals ; Antineoplastic Agents - pharmacology ; Antitumor activity ; Apoptosis ; Apoptosis - drug effects ; Azepines - pharmacology ; c-Myc protein ; Cancer ; Carcinoma, Pancreatic Ductal - pathology ; Cdc25B phosphatase ; Cell Biology ; Cell cycle ; Development and progression ; Gene expression ; Gene Expression - drug effects ; Genes, myc ; Genetic aspects ; Health aspects ; Human Genetics ; Humans ; Immunoblotting ; Immunohistochemistry ; Internal Medicine ; Medicine ; Medicine & Public Health ; Mice ; Mice, SCID ; Myc protein ; Nerve Tissue Proteins - antagonists & inhibitors ; Oligonucleotide Array Sequence Analysis ; Oncogenes ; Oncology ; original-article ; Pancreas ; Pancreatic cancer ; Pancreatic Neoplasms - pathology ; Patients ; Pharmaceutical sciences ; Polymerase Chain Reaction ; Protein expression ; Receptors, Cell Surface - antagonists & inhibitors ; Tissue inhibitor of metalloproteinase 3 ; Triazoles - pharmacology ; Tumors ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>Oncogene, 2016-02, Vol.35 (7), p.833-845</ispartof><rights>Macmillan Publishers Limited 2016</rights><rights>COPYRIGHT 2016 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Feb 18, 2016</rights><rights>Macmillan Publishers Limited 2016.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c714t-13a5104120c65483c3e21b69b86b3434753d8551203e1ea5b4a560db4ee82c7f3</citedby><cites>FETCH-LOGICAL-c714t-13a5104120c65483c3e21b69b86b3434753d8551203e1ea5b4a560db4ee82c7f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/onc.2015.126$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2015.126$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25961927$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Garcia, P L</creatorcontrib><creatorcontrib>Miller, A L</creatorcontrib><creatorcontrib>Kreitzburg, K M</creatorcontrib><creatorcontrib>Council, L N</creatorcontrib><creatorcontrib>Gamblin, T L</creatorcontrib><creatorcontrib>Christein, J D</creatorcontrib><creatorcontrib>Heslin, M J</creatorcontrib><creatorcontrib>Arnoletti, J P</creatorcontrib><creatorcontrib>Richardson, J H</creatorcontrib><creatorcontrib>Chen, D</creatorcontrib><creatorcontrib>Hanna, C A</creatorcontrib><creatorcontrib>Cramer, S L</creatorcontrib><creatorcontrib>Yang, E S</creatorcontrib><creatorcontrib>Qi, J</creatorcontrib><creatorcontrib>Bradner, J E</creatorcontrib><creatorcontrib>Yoon, K J</creatorcontrib><title>The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT–PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (
P
<0.05), each of which harbors a KRAS mutation; but induced no consistent change in expression of c-Myc protein. Expression profiling identified CDC25B, a regulator of cell cycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (
P
<0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1.</description><subject>13/1</subject><subject>13/51</subject><subject>14/63</subject><subject>45/77</subject><subject>631/67/1059/602</subject><subject>64/60</subject><subject>82/29</subject><subject>Adenocarcinoma</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Azepines - pharmacology</subject><subject>c-Myc protein</subject><subject>Cancer</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>Cdc25B phosphatase</subject><subject>Cell Biology</subject><subject>Cell cycle</subject><subject>Development and progression</subject><subject>Gene expression</subject><subject>Gene Expression - drug effects</subject><subject>Genes, myc</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Immunohistochemistry</subject><subject>Internal Medicine</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, SCID</subject><subject>Myc protein</subject><subject>Nerve Tissue Proteins - antagonists & inhibitors</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Oncogenes</subject><subject>Oncology</subject><subject>original-article</subject><subject>Pancreas</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Patients</subject><subject>Pharmaceutical sciences</subject><subject>Polymerase Chain Reaction</subject><subject>Protein expression</subject><subject>Receptors, Cell Surface - antagonists & inhibitors</subject><subject>Tissue inhibitor of metalloproteinase 3</subject><subject>Triazoles - pharmacology</subject><subject>Tumors</subject><subject>Xenograft Model Antitumor 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BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models</title><author>Garcia, P L ; Miller, A L ; Kreitzburg, K M ; Council, L N ; Gamblin, T L ; Christein, J D ; Heslin, M J ; Arnoletti, J P ; Richardson, J H ; Chen, D ; Hanna, C A ; Cramer, S L ; Yang, E S ; Qi, J ; Bradner, J E ; Yoon, K J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c714t-13a5104120c65483c3e21b69b86b3434753d8551203e1ea5b4a560db4ee82c7f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>13/1</topic><topic>13/51</topic><topic>14/63</topic><topic>45/77</topic><topic>631/67/1059/602</topic><topic>64/60</topic><topic>82/29</topic><topic>Adenocarcinoma</topic><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antitumor activity</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Azepines - pharmacology</topic><topic>c-Myc protein</topic><topic>Cancer</topic><topic>Carcinoma, Pancreatic Ductal - pathology</topic><topic>Cdc25B phosphatase</topic><topic>Cell Biology</topic><topic>Cell cycle</topic><topic>Development and progression</topic><topic>Gene expression</topic><topic>Gene Expression - drug effects</topic><topic>Genes, myc</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Immunohistochemistry</topic><topic>Internal Medicine</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mice, SCID</topic><topic>Myc protein</topic><topic>Nerve Tissue Proteins - antagonists & inhibitors</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>Oncogenes</topic><topic>Oncology</topic><topic>original-article</topic><topic>Pancreas</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms - 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(Full Participant titles)</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Garcia, P L</au><au>Miller, A L</au><au>Kreitzburg, K M</au><au>Council, L N</au><au>Gamblin, T L</au><au>Christein, J D</au><au>Heslin, M J</au><au>Arnoletti, J P</au><au>Richardson, J H</au><au>Chen, D</au><au>Hanna, C A</au><au>Cramer, S L</au><au>Yang, E S</au><au>Qi, J</au><au>Bradner, J E</au><au>Yoon, K J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2016-02-18</date><risdate>2016</risdate><volume>35</volume><issue>7</issue><spage>833</spage><epage>845</epage><pages>833-845</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT–PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (
P
<0.05), each of which harbors a KRAS mutation; but induced no consistent change in expression of c-Myc protein. Expression profiling identified CDC25B, a regulator of cell cycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (
P
<0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25961927</pmid><doi>10.1038/onc.2015.126</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Oncogene, 2016-02, Vol.35 (7), p.833-845 |
| issn | 0950-9232 1476-5594 |
| language | eng |
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| source | MEDLINE; SpringerLink Journals; Nature |
| subjects | 13/1 13/51 14/63 45/77 631/67/1059/602 64/60 82/29 Adenocarcinoma Animals Antineoplastic Agents - pharmacology Antitumor activity Apoptosis Apoptosis - drug effects Azepines - pharmacology c-Myc protein Cancer Carcinoma, Pancreatic Ductal - pathology Cdc25B phosphatase Cell Biology Cell cycle Development and progression Gene expression Gene Expression - drug effects Genes, myc Genetic aspects Health aspects Human Genetics Humans Immunoblotting Immunohistochemistry Internal Medicine Medicine Medicine & Public Health Mice Mice, SCID Myc protein Nerve Tissue Proteins - antagonists & inhibitors Oligonucleotide Array Sequence Analysis Oncogenes Oncology original-article Pancreas Pancreatic cancer Pancreatic Neoplasms - pathology Patients Pharmaceutical sciences Polymerase Chain Reaction Protein expression Receptors, Cell Surface - antagonists & inhibitors Tissue inhibitor of metalloproteinase 3 Triazoles - pharmacology Tumors Xenograft Model Antitumor Assays Xenografts |
| title | The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-25T01%3A56%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20BET%20bromodomain%20inhibitor%20JQ1%20suppresses%20growth%20of%20pancreatic%20ductal%20adenocarcinoma%20in%20patient-derived%20xenograft%20models&rft.jtitle=Oncogene&rft.au=Garcia,%20P%20L&rft.date=2016-02-18&rft.volume=35&rft.issue=7&rft.spage=833&rft.epage=845&rft.pages=833-845&rft.issn=0950-9232&rft.eissn=1476-5594&rft.coden=ONCNES&rft_id=info:doi/10.1038/onc.2015.126&rft_dat=%3Cgale_pubme%3EA445019116%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1765994429&rft_id=info:pmid/25961927&rft_galeid=A445019116&rfr_iscdi=true |