Single-cell imaging analysis, therapeutic modeling and a Phase Ib trial validate BCL-2 as a target across heterogeneous castration-resistant prostate cancer

  • Signal Transduct Target Ther. 2026 May 1;11(1):161. doi: 10.1038/s41392-026-02700-w.
Anmbreen Jamroze  1 ,  Xiaozhuo Liu  2 ,  Surui Hou  3 ,  Wen Jess Li  2  4  5 ,  Han Yu  3 ,  Amanda Tracz  2 ,  Justine Jacobi  3 ,  Qiuhui Li  2  6 ,  Kent Nastiuk  7 ,  Xin Chen  2  8 ,  Jiaoti Huang  9 ,  Kevin Lin  10 ,  Mingyu Liu  11 ,  Changmeng Cai  11 ,  Yue Lu  10 ,  Igor Puzanov  12 ,  Jason S Kirk  2 ,  Gurkamal Chatta  12 ,  Dean G Tang  13  14
Affiliations
  • 1. Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. [email protected].
  • 2. Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • 3. Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • 4. Experimental Therapeutics (ET) Graduate Program, Roswell Park Comprehensive Cancer Center and the University at Buffalo, Buffalo, NY, USA.
  • 5. Department of Medicine and Department of Biomedical Sciences, Cedars-Sinai Medical Center, and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 6. State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine of Ministry of Education (KLOBM), School and Hospital of Stomatology, Wuhan University, Wuhan, China.
  • 7. Departments of Cancer Genetics and Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • 8. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 9. Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
  • 10. Department of Epigenetics and Molecular Carcinogenesis, the University of Texas M.D Anderson Cancer Center, Houston, TX, USA.
  • 11. Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, USA.
  • 12. Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • 13. Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. [email protected].
  • 14. Experimental Therapeutics (ET) Graduate Program, Roswell Park Comprehensive Cancer Center and the University at Buffalo, Buffalo, NY, USA. [email protected].
PMID: 42067541 DOI: 10.1038/s41392-026-02700-w
Abstract

Bcl-2 has been implicated in prostate Cancer (PCa) progression and development of castration-resistant disease (CRPC); however, it remains unclear how the BCL-2- and AR-expressing PCa cell populations evolve across the PCa continuum, how AR molecularly regulates Bcl-2 and whether Bcl-2 represents a common therapeutic target in heterogeneous CRPC. Here we first show the selective induction of Bcl-2 by AR pathway inhibitors (ARPIs). Vectra-based quantitative multiplex immunofluorescence (qmIF) and image mass cytometry (IMC) analyses with single-cell resolution in patient PCa and xenograft models reveal markedly increased Bcl-2+ (AR+ or AR-) PCa cells in CRPC. Mechanistically, AR represses Bcl-2 transcription through several AR binding sites and ARPIs relieve this repression. Therapeutic studies in cells, organoids and xenografts support Bcl-2 as a shared vulnerability across diverse CRPC subtypes. A Phase Ib clinical trial (NCT03751436) combining enzalutamide and Bcl-2 Inhibitor venetoclax demonstrated reduced circulating tumor cells in responding patients. In summary, by integrating high-content single-cell level imaging analyses with mechanistic studies, extensive preclinical therapeutic experiments and a Phase Ib clinical trial, our studies herein elucidate the AR+/-Bcl-2+/- PCa cell subpopulation dynamics and credentials Bcl-2 as a vital therapeutic target in heterogeneous CRPC.

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