2. Academic Validation
  3. Transcriptional profiling clarifies a program of enzalutamide extreme non-response in lethal prostate cancer

Transcriptional profiling clarifies a program of enzalutamide extreme non-response in lethal prostate cancer

  • NPJ Precis Oncol. 2025 Jul 7;9(1):223. doi: 10.1038/s41698-025-01002-8.
Anbarasu Kumaraswamy # 1 2,  Ya-Mei Hu # 3 4,  Joel A Yates # 1 2,  Chao Zhang 1 2,  Eva Rodansky 1 2,  Dhruv Khokhani 1 2,  Diana Flores 1 2,  Zhi Duan 1 2,  Yi Zhang 3 4,  Shaadi Tabatabaei 4,  Rachel Slottke 4,  Shangyuan Ye 5,  Primo Lara 6,  Adam Foye 7 8,  Charles J Ryan 9 10,  David A Quigley 7 11 12,  Jiaoti Huang 13,  Rahul Aggarwal 7 8,  Robert E Reiter 14,  Max S Wicha 1,  Tomasz M Beer 4,  Matthew Rettig 14 15,  Martin Gleave 16 17,  Christopher P Evans 6,  Owen N Witte 18,  Joshua M Stuart 19,  George V Thomas 4,  Felix Y Feng 7 20,  Eric J Small 7 8,  Zheng Xia 21 22,  Joshi J Alumkal 23 24
Affiliations

Affiliations

  • 1 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • 2 Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • 3 Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA.
  • 4 Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
  • 5 Biostatistics Shared Resource, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
  • 6 University of California Davis, Davis, CA, USA.
  • 7 Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
  • 8 Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
  • 9 Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • 10 Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA.
  • 11 Department of Urology, University of California San Francisco, San Francisco, CA, USA.
  • 12 Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, CA, USA.
  • 13 Duke University, Durham, NC, USA.
  • 14 Departments of Medicine and Urology, University of California Los Angeles, Los Angeles, CA, USA.
  • 15 Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
  • 16 Department of Urological Sciences, University of British Columbia, Vancouver, BC, Canada.
  • 17 Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
  • 18 Department of Microbiology, Immunology, and Molecular Genetics at the David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
  • 19 Genomics Institute and Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, USA.
  • 20 Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, CA, USA.
  • 21 Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA. xiaz@ohsu.edu.
  • 22 Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. xiaz@ohsu.edu.
  • 23 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. jalumkal@med.umich.edu.
  • 24 Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. jalumkal@med.umich.edu.
  • # Contributed equally.
PMID: 40624104 DOI: 10.1038/s41698-025-01002-8
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.

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