Transcriptional profiling clarifies a program of enzalutamide extreme non-response in lethal prostate cancer
Abstract The androgen receptor inhibitor enzalutamide is one of the principal treatments for metastatic prostate cancer. Most patients respond. However, a subset is primary refractory. Seeking to understand enzalutamide extreme non-response (ENR), we analyzed RNA-sequencing in biopsies from men trea...
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| Format: | Article |
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Nature Portfolio
2025-07-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-025-01002-8 |
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| author | Anbarasu Kumaraswamy Ya-Mei Hu Joel A. Yates Chao Zhang Eva Rodansky Dhruv Khokhani Diana Flores Zhi Duan Yi Zhang Shaadi Tabatabaei Rachel Slottke Shangyuan Ye Primo Lara Adam Foye Charles J. Ryan David A. Quigley Jiaoti Huang Rahul Aggarwal Robert E. Reiter Max S. Wicha Tomasz M. Beer Matthew Rettig Martin Gleave Christopher P. Evans Owen N. Witte Joshua M. Stuart George V. Thomas Felix Y. Feng Eric J. Small Zheng Xia Joshi J. Alumkal |
| author_facet | Anbarasu Kumaraswamy Ya-Mei Hu Joel A. Yates Chao Zhang Eva Rodansky Dhruv Khokhani Diana Flores Zhi Duan Yi Zhang Shaadi Tabatabaei Rachel Slottke Shangyuan Ye Primo Lara Adam Foye Charles J. Ryan David A. Quigley Jiaoti Huang Rahul Aggarwal Robert E. Reiter Max S. Wicha Tomasz M. Beer Matthew Rettig Martin Gleave Christopher P. Evans Owen N. Witte Joshua M. Stuart George V. Thomas Felix Y. Feng Eric J. Small Zheng Xia Joshi J. Alumkal |
| author_sort | Anbarasu Kumaraswamy |
| collection | DOAJ |
| description | Abstract The androgen receptor inhibitor enzalutamide is one of the principal treatments for metastatic prostate cancer. Most patients respond. However, a subset is primary refractory. Seeking to understand enzalutamide extreme non-response (ENR), we analyzed RNA-sequencing in biopsies from men treated prospectively on an enzalutamide clinical trial. We focused on those with ENR (progression within 3 months) vs. long-term response (progression after 24 months). We identified an ENR program linked to proliferation, epithelial-to-mesenchymal transition, and stemness. High expression of this program in additional datasets was independently linked to poor tumor control with AR targeting but favorable tumor control with docetaxel, another standard treatment. CDK2 was implicated in the ENR program. CDK2 suppression reduced the ENR program and viability of ENR program-high prostate cancer models. The ENR gene program is predictive of non-response to AR targeting. Patients whose tumors harbor this program may be good candidates for docetaxel or CDK2 inhibitor clinical trials. |
| format | Article |
| id | doaj-art-66f0fca4fdc6485bbbe5b8213fcf4ffd |
| institution | DOAJ |
| issn | 2397-768X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj-art-66f0fca4fdc6485bbbe5b8213fcf4ffd2025-08-20T03:04:18ZengNature Portfolionpj Precision Oncology2397-768X2025-07-019111310.1038/s41698-025-01002-8Transcriptional profiling clarifies a program of enzalutamide extreme non-response in lethal prostate cancerAnbarasu Kumaraswamy0Ya-Mei Hu1Joel A. Yates2Chao Zhang3Eva Rodansky4Dhruv Khokhani5Diana Flores6Zhi Duan7Yi Zhang8Shaadi Tabatabaei9Rachel Slottke10Shangyuan Ye11Primo Lara12Adam Foye13Charles J. Ryan14David A. Quigley15Jiaoti Huang16Rahul Aggarwal17Robert E. Reiter18Max S. Wicha19Tomasz M. Beer20Matthew Rettig21Martin Gleave22Christopher P. Evans23Owen N. Witte24Joshua M. Stuart25George V. Thomas26Felix Y. Feng27Eric J. Small28Zheng Xia29Joshi J. Alumkal30Department of Internal Medicine, University of MichiganDepartment of Biomedical Engineering, Oregon Health & Science UniversityDepartment of Internal Medicine, University of MichiganDepartment of Internal Medicine, University of MichiganDepartment of Internal Medicine, University of MichiganDepartment of Internal Medicine, University of MichiganDepartment of Internal Medicine, University of MichiganDepartment of Internal Medicine, University of MichiganDepartment of Biomedical Engineering, Oregon Health & Science UniversityKnight Cancer Institute, Oregon Health & Science UniversityKnight Cancer Institute, Oregon Health & Science UniversityBiostatistics Shared Resource, Knight Cancer Institute, Oregon Health & Science UniversityUniversity of California DavisHelen Diller Family Comprehensive Cancer Center, University of California San FranciscoMasonic Cancer Center, University of MinnesotaHelen Diller Family Comprehensive Cancer Center, University of California San FranciscoDuke UniversityHelen Diller Family Comprehensive Cancer Center, University of California San FranciscoDepartments of Medicine and Urology, University of California Los AngelesDepartment of Internal Medicine, University of MichiganKnight Cancer Institute, Oregon Health & Science UniversityDepartments of Medicine and Urology, University of California Los AngelesDepartment of Urological Sciences, University of British ColumbiaUniversity of California DavisDepartment of Microbiology, Immunology, and Molecular Genetics at the David Geffen School of Medicine, University of California Los AngelesGenomics Institute and Department of Biomolecular Engineering, University of California Santa CruzKnight Cancer Institute, Oregon Health & Science UniversityHelen Diller Family Comprehensive Cancer Center, University of California San FranciscoHelen Diller Family Comprehensive Cancer Center, University of California San FranciscoDepartment of Biomedical Engineering, Oregon Health & Science UniversityDepartment of Internal Medicine, University of MichiganAbstract The androgen receptor inhibitor enzalutamide is one of the principal treatments for metastatic prostate cancer. Most patients respond. However, a subset is primary refractory. Seeking to understand enzalutamide extreme non-response (ENR), we analyzed RNA-sequencing in biopsies from men treated prospectively on an enzalutamide clinical trial. We focused on those with ENR (progression within 3 months) vs. long-term response (progression after 24 months). We identified an ENR program linked to proliferation, epithelial-to-mesenchymal transition, and stemness. High expression of this program in additional datasets was independently linked to poor tumor control with AR targeting but favorable tumor control with docetaxel, another standard treatment. CDK2 was implicated in the ENR program. CDK2 suppression reduced the ENR program and viability of ENR program-high prostate cancer models. The ENR gene program is predictive of non-response to AR targeting. Patients whose tumors harbor this program may be good candidates for docetaxel or CDK2 inhibitor clinical trials.https://doi.org/10.1038/s41698-025-01002-8 |
| spellingShingle | Anbarasu Kumaraswamy Ya-Mei Hu Joel A. Yates Chao Zhang Eva Rodansky Dhruv Khokhani Diana Flores Zhi Duan Yi Zhang Shaadi Tabatabaei Rachel Slottke Shangyuan Ye Primo Lara Adam Foye Charles J. Ryan David A. Quigley Jiaoti Huang Rahul Aggarwal Robert E. Reiter Max S. Wicha Tomasz M. Beer Matthew Rettig Martin Gleave Christopher P. Evans Owen N. Witte Joshua M. Stuart George V. Thomas Felix Y. Feng Eric J. Small Zheng Xia Joshi J. Alumkal Transcriptional profiling clarifies a program of enzalutamide extreme non-response in lethal prostate cancer npj Precision Oncology |
| title | Transcriptional profiling clarifies a program of enzalutamide extreme non-response in lethal prostate cancer |
| title_full | Transcriptional profiling clarifies a program of enzalutamide extreme non-response in lethal prostate cancer |
| title_fullStr | Transcriptional profiling clarifies a program of enzalutamide extreme non-response in lethal prostate cancer |
| title_full_unstemmed | Transcriptional profiling clarifies a program of enzalutamide extreme non-response in lethal prostate cancer |
| title_short | Transcriptional profiling clarifies a program of enzalutamide extreme non-response in lethal prostate cancer |
| title_sort | transcriptional profiling clarifies a program of enzalutamide extreme non response in lethal prostate cancer |
| url | https://doi.org/10.1038/s41698-025-01002-8 |
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