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

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.