2. Academic Validation
  3. PlexinD1 is a driver and a therapeutic target in advanced prostate cancer

PlexinD1 is a driver and a therapeutic target in advanced prostate cancer

  • EMBO Mol Med. 2025 Feb;17(2):336-364. doi: 10.1038/s44321-024-00186-z.
Jing Wei # 1,  Jing Wang # 2 3,  Wen Guan 1,  Jingjing Li 1 4,  Tianjie Pu 1 5,  Eva Corey 6,  Tzu-Ping Lin 7 8,  Allen C Gao 9,  Boyang Jason Wu 10
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA.
  • 2 Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA. jing_wang1@dfci.harvard.edu.
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. jing_wang1@dfci.harvard.edu.
  • 4 Engineering Research Center of Cell & Therapeutic Antibody, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 5 Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 6 Department of Urology, University of Washington, Seattle, WA, 98195, USA.
  • 7 Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan, 11217, Republic of China.
  • 8 Department of Urology, School of Medicine and Shu-Tien Urological Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan, 11221, Republic of China.
  • 9 Department of Urologic Surgery, University of California, Davis, Sacramento, CA, 95817, USA.
  • 10 Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA. boyang.wu@wsu.edu.
  • # Contributed equally.
PMID: 39748059 DOI: 10.1038/s44321-024-00186-z
Abstract

Aggressive prostate Cancer (PCa) variants associated with Androgen Receptor signaling inhibitor (ARSI) resistance and metastasis remain poorly understood. Here, we identify the axon guidance semaphorin receptor PlexinD1 as a crucial driver of Cancer aggressiveness in metastatic castration-resistant prostate Cancer (CRPC). High PlexinD1 expression in human PCa is correlated with adverse clinical outcomes. PlexinD1 critically maintains CRPC aggressive behaviors in vitro and in vivo, and confers stemness and cellular plasticity to promote multilineage differentiation including a neuroendocrine-like phenotype for ARSI resistance. Mechanistically, PlexinD1 is upregulated upon relief of AR-mediated transcriptional repression of PlexinD1 under ARSI treatment, and subsdquently transactivates ErbB3 and cMet via direct interaction, which triggers the ERK/Akt pathways to induce noncanonical Gli1-dictated Hedgehog signaling, facilitating the growth and plasticity of PCa cells. Blockade of PlexinD1 by the protein inhibitor D1SP restricted CRPC growth in multiple preclinical models. Collectively, these findings characterize PlexinD1's contribution to PCa progression and offer a potential PlexinD1-targeted therapy for advanced PCa.

Keywords

Androgen Receptor Signaling inhibitors; Castration-resistant Prostate Cancer; Cellular Plasticity; Neuroendocrine Differentiation; PlexinD1.

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