Targeting the Androgen Receptor Confers In Vivo Cross-resistance Between Enzalutamide and Docetaxel, But Not Cabazitaxel, in Castration-resistant Prostate Cancer
Abstract Treatment options for metastatic castration-resistant prostate cancer (CRPC) have evolved with the established benefit of the novel androgen receptor (AR)-targeted agents abiraterone and enzalutamide in the prechemotherapy setting. However, concerns regarding cross-resistance between the ta...
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| Veröffentlicht in: | European urology 2015-06, Vol.67 (6), p.981-985 |
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| creator | van Soest, Robert J de Morrée, Ellen S Kweldam, Charlotte F de Ridder, Corrina M.A Wiemer, Erik A.C Mathijssen, Ron H.J de Wit, Ronald van Weerden, Wytske M |
| description | Abstract Treatment options for metastatic castration-resistant prostate cancer (CRPC) have evolved with the established benefit of the novel androgen receptor (AR)-targeted agents abiraterone and enzalutamide in the prechemotherapy setting. However, concerns regarding cross-resistance between the taxanes docetaxel and cabazitaxel and these AR-targeted agents have arisen, and the optimal drug treatment sequence is unknown. We investigated the in vivo efficacy of docetaxel and cabazitaxel in enzalutamide-resistant CRPC, and mechanisms of cross-resistance between these agents. Castrated mice harboring enzalutamide-resistant tumors and enzalutamide-naïve tumors were treated with docetaxel and cabazitaxel. Tumor growth kinetics, AR nuclear localization, AR-regulated gene expression, Ki67 expression, and serum levels of prostate-specific antigen, docetaxel, and cabazitaxel were analyzed. Docetaxel inhibited tumor growth, AR nuclear localization, and AR-regulated gene expression in enzalutamide-naïve tumors, but did not in enzalutamide-resistant tumors, demonstrating in vivo cross-resistance. By contrast, cabazitaxel remained highly effective in enzalutamide-resistant tumors and demonstrated superior antitumor activity compared to docetaxel, independent of the AR pathway. These findings demonstrate that the AR pathway is able to confer in vivo cross-resistance between enzalutamide and docetaxel, but not cabazitaxel, in CRPC. Patient summary We found reduced efficacy of docetaxel, but not cabazitaxel, in enzalutamide-resistant prostate cancer. |
| doi_str_mv | 10.1016/j.eururo.2014.11.033 |
| format | Article |
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However, concerns regarding cross-resistance between the taxanes docetaxel and cabazitaxel and these AR-targeted agents have arisen, and the optimal drug treatment sequence is unknown. We investigated the in vivo efficacy of docetaxel and cabazitaxel in enzalutamide-resistant CRPC, and mechanisms of cross-resistance between these agents. Castrated mice harboring enzalutamide-resistant tumors and enzalutamide-naïve tumors were treated with docetaxel and cabazitaxel. Tumor growth kinetics, AR nuclear localization, AR-regulated gene expression, Ki67 expression, and serum levels of prostate-specific antigen, docetaxel, and cabazitaxel were analyzed. Docetaxel inhibited tumor growth, AR nuclear localization, and AR-regulated gene expression in enzalutamide-naïve tumors, but did not in enzalutamide-resistant tumors, demonstrating in vivo cross-resistance. By contrast, cabazitaxel remained highly effective in enzalutamide-resistant tumors and demonstrated superior antitumor activity compared to docetaxel, independent of the AR pathway. These findings demonstrate that the AR pathway is able to confer in vivo cross-resistance between enzalutamide and docetaxel, but not cabazitaxel, in CRPC. Patient summary We found reduced efficacy of docetaxel, but not cabazitaxel, in enzalutamide-resistant prostate cancer.</description><identifier>ISSN: 0302-2838</identifier><identifier>EISSN: 1873-7560</identifier><identifier>DOI: 10.1016/j.eururo.2014.11.033</identifier><identifier>PMID: 25484141</identifier><language>eng</language><publisher>Switzerland: Elsevier B.V</publisher><subject>Aged ; Androgen receptor ; Animals ; Antineoplastic Agents - therapeutic use ; Cabazitaxel ; Castration-resistant prostate cancer ; Cross-resistance ; Disease Models, Animal ; Disease Progression ; Docetaxel ; Drug Resistance, Neoplasm ; Enzalutamide ; Humans ; Ki-67 Antigen - metabolism ; Male ; Mice ; Middle Aged ; Phenylthiohydantoin - analogs & derivatives ; Phenylthiohydantoin - therapeutic use ; Prostate-Specific Antigen - blood ; Prostatic Neoplasms, Castration-Resistant - blood ; Prostatic Neoplasms, Castration-Resistant - drug therapy ; Prostatic Neoplasms, Castration-Resistant - metabolism ; Prostatic Neoplasms, Castration-Resistant - pathology ; Receptors, Androgen - metabolism ; Taxanes ; Taxoids - therapeutic use ; Treatment Outcome ; Urology</subject><ispartof>European urology, 2015-06, Vol.67 (6), p.981-985</ispartof><rights>European Association of Urology</rights><rights>2014 European Association of Urology</rights><rights>Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-9a2adffd515b765b1bb32267de2ec726df7d412f20acac049053b8982cdb446f3</citedby><cites>FETCH-LOGICAL-c417t-9a2adffd515b765b1bb32267de2ec726df7d412f20acac049053b8982cdb446f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.eururo.2014.11.033$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25484141$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>van Soest, Robert J</creatorcontrib><creatorcontrib>de Morrée, Ellen S</creatorcontrib><creatorcontrib>Kweldam, Charlotte F</creatorcontrib><creatorcontrib>de Ridder, Corrina M.A</creatorcontrib><creatorcontrib>Wiemer, Erik A.C</creatorcontrib><creatorcontrib>Mathijssen, Ron H.J</creatorcontrib><creatorcontrib>de Wit, Ronald</creatorcontrib><creatorcontrib>van Weerden, Wytske M</creatorcontrib><title>Targeting the Androgen Receptor Confers In Vivo Cross-resistance Between Enzalutamide and Docetaxel, But Not Cabazitaxel, in Castration-resistant Prostate Cancer</title><title>European urology</title><addtitle>Eur Urol</addtitle><description>Abstract Treatment options for metastatic castration-resistant prostate cancer (CRPC) have evolved with the established benefit of the novel androgen receptor (AR)-targeted agents abiraterone and enzalutamide in the prechemotherapy setting. However, concerns regarding cross-resistance between the taxanes docetaxel and cabazitaxel and these AR-targeted agents have arisen, and the optimal drug treatment sequence is unknown. We investigated the in vivo efficacy of docetaxel and cabazitaxel in enzalutamide-resistant CRPC, and mechanisms of cross-resistance between these agents. Castrated mice harboring enzalutamide-resistant tumors and enzalutamide-naïve tumors were treated with docetaxel and cabazitaxel. Tumor growth kinetics, AR nuclear localization, AR-regulated gene expression, Ki67 expression, and serum levels of prostate-specific antigen, docetaxel, and cabazitaxel were analyzed. Docetaxel inhibited tumor growth, AR nuclear localization, and AR-regulated gene expression in enzalutamide-naïve tumors, but did not in enzalutamide-resistant tumors, demonstrating in vivo cross-resistance. By contrast, cabazitaxel remained highly effective in enzalutamide-resistant tumors and demonstrated superior antitumor activity compared to docetaxel, independent of the AR pathway. These findings demonstrate that the AR pathway is able to confer in vivo cross-resistance between enzalutamide and docetaxel, but not cabazitaxel, in CRPC. Patient summary We found reduced efficacy of docetaxel, but not cabazitaxel, in enzalutamide-resistant prostate cancer.</description><subject>Aged</subject><subject>Androgen receptor</subject><subject>Animals</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Cabazitaxel</subject><subject>Castration-resistant prostate cancer</subject><subject>Cross-resistance</subject><subject>Disease Models, Animal</subject><subject>Disease Progression</subject><subject>Docetaxel</subject><subject>Drug Resistance, Neoplasm</subject><subject>Enzalutamide</subject><subject>Humans</subject><subject>Ki-67 Antigen - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Middle Aged</subject><subject>Phenylthiohydantoin - analogs & derivatives</subject><subject>Phenylthiohydantoin - therapeutic use</subject><subject>Prostate-Specific Antigen - blood</subject><subject>Prostatic Neoplasms, Castration-Resistant - blood</subject><subject>Prostatic Neoplasms, Castration-Resistant - drug therapy</subject><subject>Prostatic Neoplasms, Castration-Resistant - metabolism</subject><subject>Prostatic Neoplasms, Castration-Resistant - pathology</subject><subject>Receptors, Androgen - metabolism</subject><subject>Taxanes</subject><subject>Taxoids - therapeutic use</subject><subject>Treatment Outcome</subject><subject>Urology</subject><issn>0302-2838</issn><issn>1873-7560</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUsuOFCEUrRiN047-gTEsXVglF6hHb0xmylEnmajR0S2h4FZLWw0tUPP6G_9UOt3Owo0rApxH7jm3KJ4DrYBC83pd4Rzm4CtGQVQAFeX8QbGAruVlWzf0YbGgnLKSdbw7Kp7EuKaU8nrJHxdHrBadAAGL4velCitM1q1I-oHkxJngV-jIF9S4TT6Q3rsRQyTnjny3V570wcdYBow2JuU0klNM15gZZ-5OTXNSG2uQKGfIW68xqRucXpHTOZGPPpFeDerOHh6ty_eYgkrWu3vFRD5nh6QS5t-sH54Wj0Y1RXx2OI-Lb-_OLvsP5cWn9-f9yUWpBbSpXCqmzDiaGuqhbeoBhoEz1rQGGeqWNWZsjQA2Mqq00lQsac2HbtkxbQYhmpEfFy_3utvgf80Yk9zYqHGalEM_RwlNR6HrRN1lqNhD9S6MgKPcBrtR4VYClbty5Fruy5G7ciSAzOVk2ouDwzxs0NyT_raRAW_2AMxzXlkMMmqLOQRjA-okjbf_c_hXQE_WWa2mn3iLce3n4HKGEmRkksqvuwXZ7QcICgwayv8A05u6Wg</recordid><startdate>20150601</startdate><enddate>20150601</enddate><creator>van Soest, Robert J</creator><creator>de Morrée, Ellen S</creator><creator>Kweldam, Charlotte F</creator><creator>de Ridder, Corrina M.A</creator><creator>Wiemer, Erik A.C</creator><creator>Mathijssen, Ron H.J</creator><creator>de Wit, Ronald</creator><creator>van Weerden, Wytske M</creator><general>Elsevier B.V</general><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>20150601</creationdate><title>Targeting the Androgen Receptor Confers In Vivo Cross-resistance Between Enzalutamide and Docetaxel, But Not Cabazitaxel, in Castration-resistant Prostate Cancer</title><author>van Soest, Robert J ; de Morrée, Ellen S ; Kweldam, Charlotte F ; de Ridder, Corrina M.A ; Wiemer, Erik A.C ; Mathijssen, Ron H.J ; de Wit, Ronald ; van Weerden, Wytske M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-9a2adffd515b765b1bb32267de2ec726df7d412f20acac049053b8982cdb446f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Aged</topic><topic>Androgen receptor</topic><topic>Animals</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Cabazitaxel</topic><topic>Castration-resistant prostate cancer</topic><topic>Cross-resistance</topic><topic>Disease Models, Animal</topic><topic>Disease Progression</topic><topic>Docetaxel</topic><topic>Drug Resistance, Neoplasm</topic><topic>Enzalutamide</topic><topic>Humans</topic><topic>Ki-67 Antigen - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Middle Aged</topic><topic>Phenylthiohydantoin - analogs & derivatives</topic><topic>Phenylthiohydantoin - therapeutic use</topic><topic>Prostate-Specific Antigen - blood</topic><topic>Prostatic Neoplasms, Castration-Resistant - blood</topic><topic>Prostatic Neoplasms, Castration-Resistant - drug therapy</topic><topic>Prostatic Neoplasms, Castration-Resistant - metabolism</topic><topic>Prostatic Neoplasms, Castration-Resistant - pathology</topic><topic>Receptors, Androgen - metabolism</topic><topic>Taxanes</topic><topic>Taxoids - therapeutic use</topic><topic>Treatment Outcome</topic><topic>Urology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>van Soest, Robert J</creatorcontrib><creatorcontrib>de Morrée, Ellen S</creatorcontrib><creatorcontrib>Kweldam, Charlotte F</creatorcontrib><creatorcontrib>de Ridder, Corrina M.A</creatorcontrib><creatorcontrib>Wiemer, Erik A.C</creatorcontrib><creatorcontrib>Mathijssen, Ron H.J</creatorcontrib><creatorcontrib>de Wit, Ronald</creatorcontrib><creatorcontrib>van Weerden, Wytske M</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>European urology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>van Soest, Robert J</au><au>de Morrée, Ellen S</au><au>Kweldam, Charlotte F</au><au>de Ridder, Corrina M.A</au><au>Wiemer, Erik A.C</au><au>Mathijssen, Ron H.J</au><au>de Wit, Ronald</au><au>van Weerden, Wytske M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting the Androgen Receptor Confers In Vivo Cross-resistance Between Enzalutamide and Docetaxel, But Not Cabazitaxel, in Castration-resistant Prostate Cancer</atitle><jtitle>European urology</jtitle><addtitle>Eur Urol</addtitle><date>2015-06-01</date><risdate>2015</risdate><volume>67</volume><issue>6</issue><spage>981</spage><epage>985</epage><pages>981-985</pages><issn>0302-2838</issn><eissn>1873-7560</eissn><abstract>Abstract Treatment options for metastatic castration-resistant prostate cancer (CRPC) have evolved with the established benefit of the novel androgen receptor (AR)-targeted agents abiraterone and enzalutamide in the prechemotherapy setting. However, concerns regarding cross-resistance between the taxanes docetaxel and cabazitaxel and these AR-targeted agents have arisen, and the optimal drug treatment sequence is unknown. We investigated the in vivo efficacy of docetaxel and cabazitaxel in enzalutamide-resistant CRPC, and mechanisms of cross-resistance between these agents. Castrated mice harboring enzalutamide-resistant tumors and enzalutamide-naïve tumors were treated with docetaxel and cabazitaxel. Tumor growth kinetics, AR nuclear localization, AR-regulated gene expression, Ki67 expression, and serum levels of prostate-specific antigen, docetaxel, and cabazitaxel were analyzed. Docetaxel inhibited tumor growth, AR nuclear localization, and AR-regulated gene expression in enzalutamide-naïve tumors, but did not in enzalutamide-resistant tumors, demonstrating in vivo cross-resistance. By contrast, cabazitaxel remained highly effective in enzalutamide-resistant tumors and demonstrated superior antitumor activity compared to docetaxel, independent of the AR pathway. These findings demonstrate that the AR pathway is able to confer in vivo cross-resistance between enzalutamide and docetaxel, but not cabazitaxel, in CRPC. Patient summary We found reduced efficacy of docetaxel, but not cabazitaxel, in enzalutamide-resistant prostate cancer.</abstract><cop>Switzerland</cop><pub>Elsevier B.V</pub><pmid>25484141</pmid><doi>10.1016/j.eururo.2014.11.033</doi><tpages>5</tpages></addata></record> |
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| subjects | Aged Androgen receptor Animals Antineoplastic Agents - therapeutic use Cabazitaxel Castration-resistant prostate cancer Cross-resistance Disease Models, Animal Disease Progression Docetaxel Drug Resistance, Neoplasm Enzalutamide Humans Ki-67 Antigen - metabolism Male Mice Middle Aged Phenylthiohydantoin - analogs & derivatives Phenylthiohydantoin - therapeutic use Prostate-Specific Antigen - blood Prostatic Neoplasms, Castration-Resistant - blood Prostatic Neoplasms, Castration-Resistant - drug therapy Prostatic Neoplasms, Castration-Resistant - metabolism Prostatic Neoplasms, Castration-Resistant - pathology Receptors, Androgen - metabolism Taxanes Taxoids - therapeutic use Treatment Outcome Urology |
| title | Targeting the Androgen Receptor Confers In Vivo Cross-resistance Between Enzalutamide and Docetaxel, But Not Cabazitaxel, in Castration-resistant Prostate Cancer |
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