Combination of androgen receptor inhibitor enzalutamide with the CDK4/6 inhibitor ribociclib in triple negative breast cancer cells
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) that currently lacks specific therapy options. Thus, chemotherapy continues to be the primary treatment, and developing novel targets is a top clinical focus. The androgen receptor (AR) has emerged as a therapeutic t...
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description | Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) that currently lacks specific therapy options. Thus, chemotherapy continues to be the primary treatment, and developing novel targets is a top clinical focus. The androgen receptor (AR) has emerged as a therapeutic target in a subtype of TNBC, with substantial clinical benefits shown in various clinical studies. Numerous studies have shown that cancer is associated with changes in components of the cell cycle machinery. Although cell cycle cyclin-dependent kinase (CDK) 4/6 inhibitors are successful in the treatment of ER-positive BC, they are not helpful in the treatment of patients with TNBC. We investigated the possibility of combining CDK4/6 inhibitor(ribociclib) with AR inhibitor(enzalutamide) in the AR-positive TNBC cell line. Ribociclib showed an inhibitory effect in TNBC cells. Additionally, we found that enzalutamide reduced cell migration/invasion, clonogenic capacity, cell cycle progression, and cell growth in AR-positive cells. Enzalutamide therapy could increase the cytostatic impact of ribociclib in AR+ TNBC cells. Furthermore, dual inhibition of AR and CDK4/6 demonstrated synergy in an AR+ TNBC model compared to each treatment alone. |
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Thus, chemotherapy continues to be the primary treatment, and developing novel targets is a top clinical focus. The androgen receptor (AR) has emerged as a therapeutic target in a subtype of TNBC, with substantial clinical benefits shown in various clinical studies. Numerous studies have shown that cancer is associated with changes in components of the cell cycle machinery. Although cell cycle cyclin-dependent kinase (CDK) 4/6 inhibitors are successful in the treatment of ER-positive BC, they are not helpful in the treatment of patients with TNBC. We investigated the possibility of combining CDK4/6 inhibitor(ribociclib) with AR inhibitor(enzalutamide) in the AR-positive TNBC cell line. Ribociclib showed an inhibitory effect in TNBC cells. Additionally, we found that enzalutamide reduced cell migration/invasion, clonogenic capacity, cell cycle progression, and cell growth in AR-positive cells. Enzalutamide therapy could increase the cytostatic impact of ribociclib in AR+ TNBC cells. Furthermore, dual inhibition of AR and CDK4/6 demonstrated synergy in an AR+ TNBC model compared to each treatment alone.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0279522</identifier><identifier>PMID: 36548336</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Androgen Receptor Antagonists - therapeutic use ; Androgen receptors ; Androgens ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Biology and Life Sciences ; Breast cancer ; Cell cycle ; Cell Line, Tumor ; Cell migration ; Chemotherapy ; Chemotherapy, Combination ; Computer and Information Sciences ; Cyclin-dependent kinase 4 ; Cyclin-Dependent Kinase 4 - antagonists & inhibitors ; Cyclin-Dependent Kinase 6 - antagonists & inhibitors ; Cyclin-dependent kinases ; Engineering and Technology ; FDA approval ; Gene expression ; Humans ; Kinases ; Medical prognosis ; Medicine and Health Sciences ; Ontology ; Prostate cancer ; Protein Kinase Inhibitors - therapeutic use ; Proteins ; Receptors ; Receptors, Androgen - metabolism ; Research and Analysis Methods ; Targeted cancer therapy ; Therapeutic targets ; Triple Negative Breast Neoplasms - drug therapy</subject><ispartof>PloS one, 2022-12, Vol.17 (12), p.e0279522-e0279522</ispartof><rights>Copyright: © 2022 Choupani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>COPYRIGHT 2022 Public Library of Science</rights><rights>2022 Choupani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Choupani, Edris</au><au>Madjd, Zahra</au><au>Saraygord-Afshari, Neda</au><au>Kiani, Jafar</au><au>Hosseini, Arshad</au><au>Migliaccio, Antimo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combination of androgen receptor inhibitor enzalutamide with the CDK4/6 inhibitor ribociclib in triple negative breast cancer cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2022-12-22</date><risdate>2022</risdate><volume>17</volume><issue>12</issue><spage>e0279522</spage><epage>e0279522</epage><pages>e0279522-e0279522</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) that currently lacks specific therapy options. Thus, chemotherapy continues to be the primary treatment, and developing novel targets is a top clinical focus. The androgen receptor (AR) has emerged as a therapeutic target in a subtype of TNBC, with substantial clinical benefits shown in various clinical studies. Numerous studies have shown that cancer is associated with changes in components of the cell cycle machinery. Although cell cycle cyclin-dependent kinase (CDK) 4/6 inhibitors are successful in the treatment of ER-positive BC, they are not helpful in the treatment of patients with TNBC. We investigated the possibility of combining CDK4/6 inhibitor(ribociclib) with AR inhibitor(enzalutamide) in the AR-positive TNBC cell line. Ribociclib showed an inhibitory effect in TNBC cells. Additionally, we found that enzalutamide reduced cell migration/invasion, clonogenic capacity, cell cycle progression, and cell growth in AR-positive cells. Enzalutamide therapy could increase the cytostatic impact of ribociclib in AR+ TNBC cells. Furthermore, dual inhibition of AR and CDK4/6 demonstrated synergy in an AR+ TNBC model compared to each treatment alone.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>36548336</pmid><doi>10.1371/journal.pone.0279522</doi><tpages>e0279522</tpages><orcidid>https://orcid.org/0000-0002-2077-0817</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Androgen Receptor Antagonists - therapeutic use Androgen receptors Androgens Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biology and Life Sciences Breast cancer Cell cycle Cell Line, Tumor Cell migration Chemotherapy Chemotherapy, Combination Computer and Information Sciences Cyclin-dependent kinase 4 Cyclin-Dependent Kinase 4 - antagonists & inhibitors Cyclin-Dependent Kinase 6 - antagonists & inhibitors Cyclin-dependent kinases Engineering and Technology FDA approval Gene expression Humans Kinases Medical prognosis Medicine and Health Sciences Ontology Prostate cancer Protein Kinase Inhibitors - therapeutic use Proteins Receptors Receptors, Androgen - metabolism Research and Analysis Methods Targeted cancer therapy Therapeutic targets Triple Negative Breast Neoplasms - drug therapy |
title | Combination of androgen receptor inhibitor enzalutamide with the CDK4/6 inhibitor ribociclib in triple negative breast cancer cells |
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