ERRγ impedes neuroendocrine prostate cancer development

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Neuroendocrine prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (CRPC).
• The molecular drivers of CRPC progression to NEPC are not fully understood.
• Effective treatments for NEPC are urgently needed.

Purpose of the Study:

• To investigate the role of the nuclear receptor ERRγ in prostate cancer progression to NEPC.
• To identify potential therapeutic targets for NEPC based on ERRγ function.

Main Methods:

• Utilized a Pten-deficient mouse model of prostate adenocarcinoma.
• Employed advanced cellular and xenograft models of human prostate cancer.
• Investigated ERRγ gain-of-function and loss-of-function effects.
• Analyzed neuroendocrine transcriptional programs and metabolic reprogramming.
• Evaluated combined pharmacological inhibition of EZH2 and RET kinase.

Main Results:

• Loss of ERRγ promotes neuroendocrine differentiation in prostate adenocarcinoma.
• ERRγ gain of function reverses NEPC features, suppresses tumor growth, and alters metabolism.
• ERRγ deficiency activates a neuroendocrine transcriptional program.
• Combined EZH2 and RET kinase inhibition effectively targets ERRγ-deficient NEPC cells and organoids.

Conclusions:

• ERRγ downregulation is a key facilitator of prostate cancer adeno-to-neuroendocrine transformation.
• Targeting the vulnerability created by ERRγ deficiency offers a promising therapeutic strategy for NEPC.
• Pharmacological inhibition of EZH2 and RET kinase presents a potential treatment for NEPC.