npj Precision Oncology (Jul 2025)
Transcriptional profiling clarifies a program of enzalutamide extreme non-response in lethal prostate cancer
- 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
Affiliations
- Anbarasu Kumaraswamy
- Department of Internal Medicine, University of Michigan
- Ya-Mei Hu
- Department of Biomedical Engineering, Oregon Health & Science University
- Joel A. Yates
- Department of Internal Medicine, University of Michigan
- Chao Zhang
- Department of Internal Medicine, University of Michigan
- Eva Rodansky
- Department of Internal Medicine, University of Michigan
- Dhruv Khokhani
- Department of Internal Medicine, University of Michigan
- Diana Flores
- Department of Internal Medicine, University of Michigan
- Zhi Duan
- Department of Internal Medicine, University of Michigan
- Yi Zhang
- Department of Biomedical Engineering, Oregon Health & Science University
- Shaadi Tabatabaei
- Knight Cancer Institute, Oregon Health & Science University
- Rachel Slottke
- Knight Cancer Institute, Oregon Health & Science University
- Shangyuan Ye
- Biostatistics Shared Resource, Knight Cancer Institute, Oregon Health & Science University
- Primo Lara
- University of California Davis
- Adam Foye
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
- Charles J. Ryan
- Masonic Cancer Center, University of Minnesota
- David A. Quigley
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
- Jiaoti Huang
- Duke University
- Rahul Aggarwal
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
- Robert E. Reiter
- Departments of Medicine and Urology, University of California Los Angeles
- Max S. Wicha
- Department of Internal Medicine, University of Michigan
- Tomasz M. Beer
- Knight Cancer Institute, Oregon Health & Science University
- Matthew Rettig
- Departments of Medicine and Urology, University of California Los Angeles
- Martin Gleave
- Department of Urological Sciences, University of British Columbia
- Christopher P. Evans
- University of California Davis
- Owen N. Witte
- Department of Microbiology, Immunology, and Molecular Genetics at the David Geffen School of Medicine, University of California Los Angeles
- Joshua M. Stuart
- Genomics Institute and Department of Biomolecular Engineering, University of California Santa Cruz
- George V. Thomas
- Knight Cancer Institute, Oregon Health & Science University
- Felix Y. Feng
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
- Eric J. Small
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
- Zheng Xia
- Department of Biomedical Engineering, Oregon Health & Science University
- Joshi J. Alumkal
- Department of Internal Medicine, University of Michigan
- DOI
- https://doi.org/10.1038/s41698-025-01002-8
- Journal volume & issue
-
Vol. 9,
no. 1
pp. 1 – 13
Abstract
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.
