Cross-Resistance Among Next-Generation Antiandrogen Drugs Through the AKR1C3/AR-V7 Axis in Advanced Prostate Cancer
The next-generation antiandrogen drugs, XTANDI (enzalutamide), ZYTIGA (abiraterone acetate), ERLEADA (apalutamide) and NUBEQA (darolutamide) extend survival times and improve quality of life in patients with advanced prostate cancer. Despite these advances, resistance occurs frequently and there is...
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| Veröffentlicht in: | Molecular cancer therapeutics 2020-08, Vol.19 (8), p.1708-1718 |
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| container_title | Molecular cancer therapeutics |
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| creator | Zhao, Jinge Ning, Shu Lou, Wei Yang, Joy C Armstrong, Cameron M Lombard, Alan P D'Abronzo, Leandro S Evans, Christopher P Gao, Allen C Liu, Chengfei |
| description | The next-generation antiandrogen drugs, XTANDI (enzalutamide), ZYTIGA (abiraterone acetate), ERLEADA (apalutamide) and NUBEQA (darolutamide) extend survival times and improve quality of life in patients with advanced prostate cancer. Despite these advances, resistance occurs frequently and there is currently no definitive cure for castration-resistant prostate cancer. Our previous studies identified that similar mechanisms of resistance to enzalutamide or abiraterone occur following treatment and cross-resistance exists between these therapies in advanced prostate cancer. Here, we show that enzalutamide- and abiraterone-resistant prostate cancer cells are further cross-resistant to apalutamide and darolutamide. Mechanistically, we have determined that the AKR1C3/AR-V7 axis confers this cross-resistance. Knockdown of AR-V7 in enzalutamide-resistant cells resensitize cells to apalutamide and darolutamide treatment. Furthermore, targeting AKR1C3 resensitizes resistant cells to apalutamide and darolutamide treatment through AR-V7 inhibition. Chronic apalutamide treatment in C4-2B cells activates the steroid hormone biosynthesis pathway and increases AKR1C3 expression, which confers resistance to enzalutamide, abiraterone, and darolutamide. In conclusion, our results suggest that apalutamide and darolutamide share similar resistant mechanisms with enzalutamide and abiraterone. The AKR1C3/AR-V7 complex confers cross-resistance to second-generation androgen receptor-targeted therapies in advanced prostate cancer. |
| doi_str_mv | 10.1158/1535-7163.MCT-20-0015 |
| format | Article |
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Despite these advances, resistance occurs frequently and there is currently no definitive cure for castration-resistant prostate cancer. Our previous studies identified that similar mechanisms of resistance to enzalutamide or abiraterone occur following treatment and cross-resistance exists between these therapies in advanced prostate cancer. Here, we show that enzalutamide- and abiraterone-resistant prostate cancer cells are further cross-resistant to apalutamide and darolutamide. Mechanistically, we have determined that the AKR1C3/AR-V7 axis confers this cross-resistance. Knockdown of AR-V7 in enzalutamide-resistant cells resensitize cells to apalutamide and darolutamide treatment. Furthermore, targeting AKR1C3 resensitizes resistant cells to apalutamide and darolutamide treatment through AR-V7 inhibition. Chronic apalutamide treatment in C4-2B cells activates the steroid hormone biosynthesis pathway and increases AKR1C3 expression, which confers resistance to enzalutamide, abiraterone, and darolutamide. In conclusion, our results suggest that apalutamide and darolutamide share similar resistant mechanisms with enzalutamide and abiraterone. The AKR1C3/AR-V7 complex confers cross-resistance to second-generation androgen receptor-targeted therapies in advanced prostate cancer.</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>DOI: 10.1158/1535-7163.MCT-20-0015</identifier><identifier>PMID: 32430485</identifier><language>eng</language><publisher>United States</publisher><subject>Aldo-Keto Reductase Family 1 Member C3 - genetics ; Aldo-Keto Reductase Family 1 Member C3 - metabolism ; Alternative Splicing ; Androgen Receptor Antagonists - classification ; Androgen Receptor Antagonists - pharmacology ; Apoptosis ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - metabolism ; Cell Proliferation ; Drug Resistance, Neoplasm ; Gene Expression Regulation, Neoplastic - drug effects ; Humans ; Male ; Prostatic Neoplasms, Castration-Resistant - drug therapy ; Prostatic Neoplasms, Castration-Resistant - genetics ; Prostatic Neoplasms, Castration-Resistant - pathology ; Receptors, Androgen - chemistry ; Receptors, Androgen - genetics ; Tumor Cells, Cultured</subject><ispartof>Molecular cancer therapeutics, 2020-08, Vol.19 (8), p.1708-1718</ispartof><rights>2020 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c422t-488e916f034073640cc79c5d7a8adf0b9e2728c28c793af06db162c73478b9013</citedby><cites>FETCH-LOGICAL-c422t-488e916f034073640cc79c5d7a8adf0b9e2728c28c793af06db162c73478b9013</cites><orcidid>0000-0002-6514-0376</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32430485$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhao, Jinge</creatorcontrib><creatorcontrib>Ning, Shu</creatorcontrib><creatorcontrib>Lou, Wei</creatorcontrib><creatorcontrib>Yang, Joy C</creatorcontrib><creatorcontrib>Armstrong, Cameron M</creatorcontrib><creatorcontrib>Lombard, Alan P</creatorcontrib><creatorcontrib>D'Abronzo, Leandro S</creatorcontrib><creatorcontrib>Evans, Christopher P</creatorcontrib><creatorcontrib>Gao, Allen C</creatorcontrib><creatorcontrib>Liu, Chengfei</creatorcontrib><title>Cross-Resistance Among Next-Generation Antiandrogen Drugs Through the AKR1C3/AR-V7 Axis in Advanced Prostate Cancer</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>The next-generation antiandrogen drugs, XTANDI (enzalutamide), ZYTIGA (abiraterone acetate), ERLEADA (apalutamide) and NUBEQA (darolutamide) extend survival times and improve quality of life in patients with advanced prostate cancer. Despite these advances, resistance occurs frequently and there is currently no definitive cure for castration-resistant prostate cancer. Our previous studies identified that similar mechanisms of resistance to enzalutamide or abiraterone occur following treatment and cross-resistance exists between these therapies in advanced prostate cancer. Here, we show that enzalutamide- and abiraterone-resistant prostate cancer cells are further cross-resistant to apalutamide and darolutamide. Mechanistically, we have determined that the AKR1C3/AR-V7 axis confers this cross-resistance. Knockdown of AR-V7 in enzalutamide-resistant cells resensitize cells to apalutamide and darolutamide treatment. Furthermore, targeting AKR1C3 resensitizes resistant cells to apalutamide and darolutamide treatment through AR-V7 inhibition. Chronic apalutamide treatment in C4-2B cells activates the steroid hormone biosynthesis pathway and increases AKR1C3 expression, which confers resistance to enzalutamide, abiraterone, and darolutamide. In conclusion, our results suggest that apalutamide and darolutamide share similar resistant mechanisms with enzalutamide and abiraterone. The AKR1C3/AR-V7 complex confers cross-resistance to second-generation androgen receptor-targeted therapies in advanced prostate cancer.</description><subject>Aldo-Keto Reductase Family 1 Member C3 - genetics</subject><subject>Aldo-Keto Reductase Family 1 Member C3 - metabolism</subject><subject>Alternative Splicing</subject><subject>Androgen Receptor Antagonists - classification</subject><subject>Androgen Receptor Antagonists - pharmacology</subject><subject>Apoptosis</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Cell Proliferation</subject><subject>Drug Resistance, Neoplasm</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Humans</subject><subject>Male</subject><subject>Prostatic Neoplasms, Castration-Resistant - drug therapy</subject><subject>Prostatic Neoplasms, Castration-Resistant - genetics</subject><subject>Prostatic Neoplasms, Castration-Resistant - pathology</subject><subject>Receptors, Androgen - chemistry</subject><subject>Receptors, Androgen - genetics</subject><subject>Tumor Cells, Cultured</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMlOwzAURS0EgjJ8AshLNi4eY2cZhVGUQVVha7mO0wa1CdgOKn-PQwHpSW_QvfdJB4BTgseECHVBBBNIkoyNH8oZohhhTMQOGKW7QkoQvvszbzUH4DCEt6RQOSX74IBRzjBXYgRC6bsQ0NSFJkTTWgeLddcu4KPbRHTjWudNbLoWFm1sTFv5buFaeOn7RYCzpe_6xRLGZTLdT0nJLoopepWw2DQBNslTfQ6JFXxOP6KJDpbD7o_BXm1WwZ389iPwcn01K2_R5OnmriwmyHJKI-JKuZxkNWYcS5ZxbK3MraikUaaq8Tx3VFJlU8mcmRpn1Zxk1ErGpZrnmLAjcL7NfffdR-9C1OsmWLdamdZ1fdCUY8FSOmVJKrZSO-Dwrtbvvlkb_6UJ1gNvPbDUA0udeGuK9cA7-c5-X_Tztav-XX-A2Tdvw3oh</recordid><startdate>202008</startdate><enddate>202008</enddate><creator>Zhao, Jinge</creator><creator>Ning, Shu</creator><creator>Lou, Wei</creator><creator>Yang, Joy C</creator><creator>Armstrong, Cameron M</creator><creator>Lombard, Alan P</creator><creator>D'Abronzo, Leandro S</creator><creator>Evans, Christopher P</creator><creator>Gao, Allen C</creator><creator>Liu, Chengfei</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><orcidid>https://orcid.org/0000-0002-6514-0376</orcidid></search><sort><creationdate>202008</creationdate><title>Cross-Resistance Among Next-Generation Antiandrogen Drugs Through the AKR1C3/AR-V7 Axis in Advanced Prostate Cancer</title><author>Zhao, Jinge ; Ning, Shu ; Lou, Wei ; Yang, Joy C ; Armstrong, Cameron M ; Lombard, Alan P ; D'Abronzo, Leandro S ; Evans, Christopher P ; Gao, Allen C ; Liu, Chengfei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c422t-488e916f034073640cc79c5d7a8adf0b9e2728c28c793af06db162c73478b9013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Aldo-Keto Reductase Family 1 Member C3 - genetics</topic><topic>Aldo-Keto Reductase Family 1 Member C3 - metabolism</topic><topic>Alternative Splicing</topic><topic>Androgen Receptor Antagonists - classification</topic><topic>Androgen Receptor Antagonists - pharmacology</topic><topic>Apoptosis</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Cell Proliferation</topic><topic>Drug Resistance, Neoplasm</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Humans</topic><topic>Male</topic><topic>Prostatic Neoplasms, Castration-Resistant - drug therapy</topic><topic>Prostatic Neoplasms, Castration-Resistant - genetics</topic><topic>Prostatic Neoplasms, Castration-Resistant - pathology</topic><topic>Receptors, Androgen - chemistry</topic><topic>Receptors, Androgen - genetics</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhao, Jinge</creatorcontrib><creatorcontrib>Ning, Shu</creatorcontrib><creatorcontrib>Lou, Wei</creatorcontrib><creatorcontrib>Yang, Joy C</creatorcontrib><creatorcontrib>Armstrong, Cameron M</creatorcontrib><creatorcontrib>Lombard, Alan P</creatorcontrib><creatorcontrib>D'Abronzo, Leandro S</creatorcontrib><creatorcontrib>Evans, Christopher P</creatorcontrib><creatorcontrib>Gao, Allen C</creatorcontrib><creatorcontrib>Liu, Chengfei</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>Zhao, Jinge</au><au>Ning, Shu</au><au>Lou, Wei</au><au>Yang, Joy C</au><au>Armstrong, Cameron M</au><au>Lombard, Alan P</au><au>D'Abronzo, Leandro S</au><au>Evans, Christopher P</au><au>Gao, Allen C</au><au>Liu, Chengfei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cross-Resistance Among Next-Generation Antiandrogen Drugs Through the AKR1C3/AR-V7 Axis in Advanced Prostate Cancer</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2020-08</date><risdate>2020</risdate><volume>19</volume><issue>8</issue><spage>1708</spage><epage>1718</epage><pages>1708-1718</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><abstract>The next-generation antiandrogen drugs, XTANDI (enzalutamide), ZYTIGA (abiraterone acetate), ERLEADA (apalutamide) and NUBEQA (darolutamide) extend survival times and improve quality of life in patients with advanced prostate cancer. Despite these advances, resistance occurs frequently and there is currently no definitive cure for castration-resistant prostate cancer. Our previous studies identified that similar mechanisms of resistance to enzalutamide or abiraterone occur following treatment and cross-resistance exists between these therapies in advanced prostate cancer. Here, we show that enzalutamide- and abiraterone-resistant prostate cancer cells are further cross-resistant to apalutamide and darolutamide. Mechanistically, we have determined that the AKR1C3/AR-V7 axis confers this cross-resistance. Knockdown of AR-V7 in enzalutamide-resistant cells resensitize cells to apalutamide and darolutamide treatment. Furthermore, targeting AKR1C3 resensitizes resistant cells to apalutamide and darolutamide treatment through AR-V7 inhibition. Chronic apalutamide treatment in C4-2B cells activates the steroid hormone biosynthesis pathway and increases AKR1C3 expression, which confers resistance to enzalutamide, abiraterone, and darolutamide. In conclusion, our results suggest that apalutamide and darolutamide share similar resistant mechanisms with enzalutamide and abiraterone. The AKR1C3/AR-V7 complex confers cross-resistance to second-generation androgen receptor-targeted therapies in advanced prostate cancer.</abstract><cop>United States</cop><pmid>32430485</pmid><doi>10.1158/1535-7163.MCT-20-0015</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-6514-0376</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Aldo-Keto Reductase Family 1 Member C3 - genetics Aldo-Keto Reductase Family 1 Member C3 - metabolism Alternative Splicing Androgen Receptor Antagonists - classification Androgen Receptor Antagonists - pharmacology Apoptosis Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Cell Proliferation Drug Resistance, Neoplasm Gene Expression Regulation, Neoplastic - drug effects Humans Male Prostatic Neoplasms, Castration-Resistant - drug therapy Prostatic Neoplasms, Castration-Resistant - genetics Prostatic Neoplasms, Castration-Resistant - pathology Receptors, Androgen - chemistry Receptors, Androgen - genetics Tumor Cells, Cultured |
| title | Cross-Resistance Among Next-Generation Antiandrogen Drugs Through the AKR1C3/AR-V7 Axis in Advanced Prostate Cancer |
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