Key genetic alterations, including those in the tumour suppressor genes RB1, TP53, and PTEN, and changes in epigenetic regulators, particularly involving EZH2 and cell-fate-determining transcription factors (TFs) such as SOX2, play significant roles in promoting NE transdifferentiation and facilitate the lineage switch from prostate adenocarcinoma to NEPC. Here, SOX2 is linked to prostate adenocarcinoma.