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Transformation of castration-resistant prostate cancer (CRPC) into an aggressive neuroendocrine disease (CRPC-NE) represents a major clinical challenge and experimental models are lacking. A CTC-derived eXplant (CDX) and a CDX-derived cell line are established using circulating tumor cells (CTCs) obtained by diagnostic leukapheresis from a CRPC patient resistant to enzalutamide. The CDX and the derived-cell line conserve 16% of primary tumor (PT) and 56% of CTC mutations, as well as 83% of PT copy-number aberrations including clonal  TMPRSS2-ERG  fusion and  NKX3.1  loss. Both harbor an androgen receptor-null neuroendocrine phenotype,  TP53, PTEN  and  RB1  loss. While  PTEN  and  RB1  loss are acquired in CTCs, evolutionary analysis suggest that a PT subclone harboring  TP53  loss is the driver of the metastatic event leading to the CDX. This CDX model provides insights on the sequential acquisition of key drivers of neuroendocrine transdifferentiation and offers a unique tool for effective drug screening in CRPC-NE management.

Genetic characterization of a unique neuroendocrine transdifferentiation prostate circulating tumor cell-derived eXplant model