PTPN1 activates neuroendocrine of treatment emergent prostate cancer by targeting the AR and REST complex

Treatment emergent neuroendocrine prostate cancer (t-NEPC) is a highly aggressive subtype of castration resistant prostate cancer (CRPC) with rapid progression and a very limited therapeutic arsenal. Clinical outcomes remain poor, and new treatment strategies with clear translational potential are urgently needed. Analyses of publicly available prostate cancer datasets showed that high PTPN1 expression is strongly associated with poor recurrence free survival in metastatic disease, suggesting that PTPN1 may serve as a clinically relevant molecular determinant of aggressive prostate cancer. We found that PTPN1 promotes t-NEPC progression and discovered a reciprocal interaction between PTPN1 and the androgen receptor and the RE1 silencing transcription factor (REST) repressor complex. This interaction represents a key regulatory mechanism driving the trans differentiation of androgen receptor positive CRPC into t-NEPC. Through CRISPR mediated PTPN1 knockout, PTPN1 cDNA overexpression, and pharmacologic inhibition in prostate cancer cells, we demonstrated that PTPN1 modulates neuroendocrine lineage plasticity. PTPN1 inhibition reduced neuroendocrine features and restored responses to anti androgen therapy in both in vitro and in vivo models. The therapeutic efficacy observed with PTPN1 inhibition highlights its translational potential as a druggable target for patients with t-NEPC, a population with urgent unmet clinical needs. These findings support further development of PTPN1 directed therapies and provide a strong rationale for future clinical investigation.