Journal Article Epublish
PubMed: 42067541 DOI: 10.1038/s41392-026-02700-w
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 11(1)
Authors: Anmbreen Jamroze, Xiaozhuo Liu, Surui Hou, Wen Jess Li, Han Yu, Amanda Tracz, Justine Jacobi, Qiuhui Li, Kent Nastiuk, Xin Chen, Jiaoti Huang, Kevin Lin, Mingyu Liu, Changmeng Cai, Yue Lu, Igor Puzanov, Jason S Kirk, Gurkamal Chatta, Dean G Tang
Affiliations
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. Experimental Therapeutics (ET) Graduate Program, Roswell Park Comprehensive Cancer Center and the University at Buffalo, Buffalo, NY, USA. 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.
- 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.
- Departments of Cancer Genetics and Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
- Department of Epigenetics and Molecular Carcinogenesis, the University of Texas M.D Anderson Cancer Center, Houston, TX, USA.
- Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, USA.
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
- Experimental Therapeutics (ET) Graduate Program, Roswell Park Comprehensive Cancer Center and the University at Buffalo, Buffalo, NY, USA.
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.
MeSH
Cells, Genes, Bcl-2, Neoplasms, Prostate, Prostatic Neoplasms, Signal Transduction, Castration, Therapeutics, Heterografts