BET Bromodomain Inhibitors Enhance Efficacy and Disrupt Resistance to AR Antagonists in the Treatment of Prostate Cancer
Next-generation antiandrogen therapies, such as enzalutamide and abiraterone, have had a profound impact on the management of metastatic castration-resistant prostate cancer (mCRPC). However, mCRPC patients invariably develop resistance to these agents. Here, a series of clonal cell lines were devel...
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| Published in | Molecular cancer research Vol. 14; no. 4; pp. 324 - 331 |
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| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
01.04.2016
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| Subjects | |
| Online Access | Get full text |
| ISSN | 1541-7786 1557-3125 1557-3125 |
| DOI | 10.1158/1541-7786.MCR-15-0472 |
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| Abstract | Next-generation antiandrogen therapies, such as enzalutamide and abiraterone, have had a profound impact on the management of metastatic castration-resistant prostate cancer (mCRPC). However, mCRPC patients invariably develop resistance to these agents. Here, a series of clonal cell lines were developed from enzalutamide-resistant prostate tumor xenografts to study the molecular mechanism of resistance and test their oncogenic potential under various treatment conditions. Androgen receptor (AR) signaling was maintained in these cell lines, which acquired potential resistance mechanisms, including expression of AR-variant 7 (AR-v7) and glucocorticoid receptor. BET bromodomain inhibitors were shown previously to attenuate AR signaling in mCRPC; here, we demonstrate the efficacy of bromodomain and extraterminal (BET) inhibitors in enzalutamide-resistant prostate cancer models. AR antagonists, enzalutamide, and ARN509 exhibit enhanced prostate tumor growth inhibition when combined with BET inhibitors, JQ1 and OTX015, respectively. Taken together, these data provide a compelling preclinical rationale to combine BET inhibitors with AR antagonists to subvert resistance mechanisms.
Implications: Therapeutic combinations of BET inhibitors and AR antagonists may enhance the clinical efficacy in the treatment of mCRPC.
Visual Overview: http://mcr.aacrjournals.org/content/14/4/324/F1.large.jpg. Mol Cancer Res; 14(4); 324–31. ©2016 AACR. |
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| AbstractList | Next-generation antiandrogen therapies, such as enzalutamide and abiraterone, have had a profound impact on the management of metastatic castration-resistant prostate cancer (mCRPC). However, mCRPC patients invariably develop resistance to these agents. Here, a series of clonal cell lines were developed from enzalutamide-resistant prostate tumor xenografts to study the molecular mechanism of resistance and test their oncogenic potential under various treatment conditions. Androgen receptor (AR) signaling was maintained in these cell lines, which acquired potential resistance mechanisms, including expression of AR-variant 7 (AR-v7) and glucocorticoid receptor. BET bromodomain inhibitors were shown previously to attenuate AR signaling in mCRPC; here, we demonstrate the efficacy of bromodomain and extraterminal (BET) inhibitors in enzalutamide-resistant prostate cancer models. AR antagonists, enzalutamide, and ARN509 exhibit enhanced prostate tumor growth inhibition when combined with BET inhibitors, JQ1 and OTX015, respectively. Taken together, these data provide a compelling preclinical rationale to combine BET inhibitors with AR antagonists to subvert resistance mechanisms.
Therapeutic combinations of BET inhibitors and AR antagonists may enhance the clinical efficacy in the treatment of mCRPC.
http://mcr.aacrjournals.org/content/molcanres/14/4/324/F1.large.jpg Next-generation antiandrogen therapies, such as enzalutamide and abiraterone, have had a profound impact on the management of metastatic castration-resistant prostate cancer (mCRPC). However, mCRPC patients invariably develop resistance to these agents. Here, a series of clonal cell lines were developed from enzalutamide-resistant prostate tumor xenografts to study the molecular mechanism of resistance and test their oncogenic potential under various treatment conditions. Androgen receptor (AR) signaling was maintained in these cell lines, which acquired potential resistance mechanisms, including expression of AR-variant 7 (AR-v7) and glucocorticoid receptor. BET bromodomain inhibitors were shown previously to attenuate AR signaling in mCRPC; here, we demonstrate the efficacy of bromodomain and extraterminal (BET) inhibitors in enzalutamide-resistant prostate cancer models. AR antagonists, enzalutamide, and ARN509 exhibit enhanced prostate tumor growth inhibition when combined with BET inhibitors, JQ1 and OTX015, respectively. Taken together, these data provide a compelling preclinical rationale to combine BET inhibitors with AR antagonists to subvert resistance mechanisms. Implications: Therapeutic combinations of BET inhibitors and AR antagonists may enhance the clinical efficacy in the treatment of mCRPC. Visual Overview: http://mcr.aacrjournals.org/content/14/4/324/F1.large.jpg. Mol Cancer Res; 14(4); 324–31. ©2016 AACR. Next-generation antiandrogen therapies, such as enzalutamide and abiraterone, have had a profound impact on the management of metastatic castration-resistant prostate cancer (mCRPC). However, mCRPC patients invariably develop resistance to these agents. Here, a series of clonal cell lines were developed from enzalutamide-resistant prostate tumor xenografts to study the molecular mechanism of resistance and test their oncogenic potential under various treatment conditions. Androgen receptor (AR) signaling was maintained in these cell lines, which acquired potential resistance mechanisms, including expression of AR-variant 7 (AR-v7) and glucocorticoid receptor. BET bromodomain inhibitors were shown previously to attenuate AR signaling in mCRPC; here, we demonstrate the efficacy of bromodomain and extraterminal (BET) inhibitors in enzalutamide-resistant prostate cancer models. AR antagonists, enzalutamide, and ARN509 exhibit enhanced prostate tumor growth inhibition when combined with BET inhibitors, JQ1 and OTX015, respectively. Taken together, these data provide a compelling preclinical rationale to combine BET inhibitors with AR antagonists to subvert resistance mechanisms.UNLABELLEDNext-generation antiandrogen therapies, such as enzalutamide and abiraterone, have had a profound impact on the management of metastatic castration-resistant prostate cancer (mCRPC). However, mCRPC patients invariably develop resistance to these agents. Here, a series of clonal cell lines were developed from enzalutamide-resistant prostate tumor xenografts to study the molecular mechanism of resistance and test their oncogenic potential under various treatment conditions. Androgen receptor (AR) signaling was maintained in these cell lines, which acquired potential resistance mechanisms, including expression of AR-variant 7 (AR-v7) and glucocorticoid receptor. BET bromodomain inhibitors were shown previously to attenuate AR signaling in mCRPC; here, we demonstrate the efficacy of bromodomain and extraterminal (BET) inhibitors in enzalutamide-resistant prostate cancer models. AR antagonists, enzalutamide, and ARN509 exhibit enhanced prostate tumor growth inhibition when combined with BET inhibitors, JQ1 and OTX015, respectively. Taken together, these data provide a compelling preclinical rationale to combine BET inhibitors with AR antagonists to subvert resistance mechanisms.Therapeutic combinations of BET inhibitors and AR antagonists may enhance the clinical efficacy in the treatment of mCRPC.IMPLICATIONSTherapeutic combinations of BET inhibitors and AR antagonists may enhance the clinical efficacy in the treatment of mCRPC.http://mcr.aacrjournals.org/content/molcanres/14/4/324/F1.large.jpgVISUAL OVERVIEWhttp://mcr.aacrjournals.org/content/molcanres/14/4/324/F1.large.jpg Next generation anti-androgen therapies such as enzalutamide and abiraterone have had a profound impact on the management of metastatic castration-resistant prostate cancer (mCRPC). However, mCRPC patients invariably develop resistance to these agents. Here, a series of clonal cell lines were developed from enzalutamide-resistant prostate tumor xenografts to study the molecular mechanism of resistance and test their oncogenic potential under various treatment conditions. Androgen receptor (AR) signaling was maintained in these cell lines which acquired potential resistance mechanisms including expression of AR-variant 7 (AR-v7) and glucocorticoid receptor (GR). BET bromodomain inhibitors were shown previously to attenuate AR signaling in mCRPC; here, we demonstrate the efficacy of BET inhibitors in enzalutamide-resistant prostate cancer models. AR antagonists, enzalutamide and ARN509 exhibit enhanced prostate tumor growth inhibition when combined with BET inhibitors, JQ1 and OTX015, respectively. Taken together, these data provide a compelling pre-clinical rationale to combine BET inhibitors with AR antagonists to subvert resistance mechanisms. |
| Author | Asangani, Irfan A. Wang, Shaomeng Chinnaiyan, Arul M. Plymate, Stephen R. Navone, Nora M. Wilder-Romans, Kari Krishnamurthy, Pranathi M. Feng, Felix Y. Dommeti, Vijaya L. Apel, Ingrid J. Escara-Wilke, June |
| AuthorAffiliation | 2 Department of Pathology, University of Michigan, Ann Arbor, Michigan 5 Department of Urology, University of Michigan, Ann Arbor, Michigan 9 Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 4 Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 6 Department of Medicine, University of Washington and VAPSHCS, Seattle 3 Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan 8 Department of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 1 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan 7 Department of Genitourinary Medical Oncology, M. D. Anderson Cancer Center, Houston |
| AuthorAffiliation_xml | – name: 1 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan – name: 6 Department of Medicine, University of Washington and VAPSHCS, Seattle – name: 8 Department of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan – name: 5 Department of Urology, University of Michigan, Ann Arbor, Michigan – name: 7 Department of Genitourinary Medical Oncology, M. D. Anderson Cancer Center, Houston – name: 9 Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan – name: 2 Department of Pathology, University of Michigan, Ann Arbor, Michigan – name: 4 Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan – name: 3 Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan |
| Author_xml | – sequence: 1 givenname: Irfan A. surname: Asangani fullname: Asangani, Irfan A. – sequence: 2 givenname: Kari surname: Wilder-Romans fullname: Wilder-Romans, Kari – sequence: 3 givenname: Vijaya L. surname: Dommeti fullname: Dommeti, Vijaya L. – sequence: 4 givenname: Pranathi M. surname: Krishnamurthy fullname: Krishnamurthy, Pranathi M. – sequence: 5 givenname: Ingrid J. surname: Apel fullname: Apel, Ingrid J. – sequence: 6 givenname: June surname: Escara-Wilke fullname: Escara-Wilke, June – sequence: 7 givenname: Stephen R. surname: Plymate fullname: Plymate, Stephen R. – sequence: 8 givenname: Nora M. surname: Navone fullname: Navone, Nora M. – sequence: 9 givenname: Shaomeng surname: Wang fullname: Wang, Shaomeng – sequence: 10 givenname: Felix Y. surname: Feng fullname: Feng, Felix Y. – sequence: 11 givenname: Arul M. surname: Chinnaiyan fullname: Chinnaiyan, Arul M. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26792867$$D View this record in MEDLINE/PubMed |
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| Snippet | Next-generation antiandrogen therapies, such as enzalutamide and abiraterone, have had a profound impact on the management of metastatic castration-resistant... Next generation anti-androgen therapies such as enzalutamide and abiraterone have had a profound impact on the management of metastatic castration-resistant... |
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| SubjectTerms | Acetanilides - administration & dosage Acetanilides - pharmacology Androgen Receptor Antagonists - administration & dosage Androgen Receptor Antagonists - pharmacology Animals Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - pharmacology Azepines - administration & dosage Azepines - pharmacology Benzamides Cell Line, Tumor Cell Proliferation - drug effects Cell Survival - drug effects Drug Resistance, Neoplasm - drug effects Heterocyclic Compounds, 3-Ring - administration & dosage Heterocyclic Compounds, 3-Ring - pharmacology Humans Male Mice Nitriles Phenylthiohydantoin - administration & dosage Phenylthiohydantoin - analogs & derivatives Phenylthiohydantoin - pharmacology Prostatic Neoplasms, Castration-Resistant - drug therapy Prostatic Neoplasms, Castration-Resistant - metabolism Receptors, Androgen - metabolism Signal Transduction - drug effects Triazoles - administration & dosage Triazoles - pharmacology Xenograft Model Antitumor Assays |
| Title | BET Bromodomain Inhibitors Enhance Efficacy and Disrupt Resistance to AR Antagonists in the Treatment of Prostate Cancer |
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