Fig. 5.

Trans-differentiation from castration-sensitive PCa to CRPC to NEPC: involvement of two generations of AR pathway-targeted agent. a ADTs mediate CRPC generation in an AR-independent manner, while ARPIs trigger NEPC formation dependent on AR signaling. ADTs blocking AR-related signaling, which exhibit remarkable activity causing tumor regression, lead to the emergence of aggressive CRPC with tumor recurrence. Likewise, the novel ARPIs by targeting specific ADT resistance contribute to tumor regression, whereas inducing a more aggressive NEPC phenotype in the process of neuroendocrine trans-differentiation promotes later acquisition of therapy resistance. b The characteristics of lineage switching from CRPC to NEPC in terms of clinical histology and molecular levels. Alteration of cellular identity from CRPC to NEPC is mainly characterized by the absence of AR and PSA. NEPC is also different from CRPC due to deletion of TP53 and RB1, enhancement of MYCN or AURKA, and upregulation of EZH2. c Aggressive behavior accompanying functional transformation from CRPC to NEPC. As lineage switching occurs, CRPC is converted to NEPC accompanied by increased invasiveness, intensive drug resistance, and elevated stem-like cell properties. CRPC castration-resistant prostate cancer, NEPC neuroendocrine prostate cancer, AR androgen receptor, ADTs androgen deprivation therapies, ARPIs AR pathway inhibitors, PSA serum prostate-specific antigen