Resistance to AR signaling inhibitors (ARSis) in a subset of metastatic castration-resistant prostate cancers (mCRPCs) occurs with the emergence of AR– neuroendocrine prostate cancer (NEPC) coupled with mutations/deletions in PTEN, TP53, and RB1 and the overexpression of DNMTs, EZH2, and/or SOX2. The gene discussed is PTEN; the disease is prostate cancer.