Loss of ERRγ promotes lineage plasticity towards neuroendocrine prostate cancer

Abstract Neuroendocrine prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (CRPC). The molecular mechanisms underlying the progression of CRPC toward NEPC remain incompletely understood and effective treatments to be discovered. Herein, we report that loss of the nuclear receptor ERRγ expression promotes neuroendocrine differentiation of PTEN-deficient prostate adenocarcinoma. Using human datasets, we first established that expression of ESRRG is downregulated in both treatment-induced and de novo NEPC. In agreement with these findings, Esrrg expression is also decreased in mouse models of the disease while prostate-specific deletion of Esrrg accelerates the development of NEPC characteristics in PTEN-deficient mice. In cellular models of human prostate cancer (PCa), rescuing ERRγ expression reverses high levels of NEPC markers, inhibits NEPC differentiation, and impedes growth of PTEN-deficient PCa cells supported by suppression of oncogenic metabolic reprogramming. Loss of ERRγ also results in the activation of a neuroendocrine transcriptional program marked by the expression of EZH2 and RET kinase whose pharmacological inhibition impedes the growth of ERRγ-deficient prostate cancer tumor organoids. Altogether, our findings reveal that loss of ERRγ drives adeno-to-neuroendocrine lineage plasticity in PCa and offer potential therapeutic strategies to prevent the development of poor outcome NEPC.