WSB1-Mediated PSMA Ubiquitination Promotes Enzalutamide-Induced Neuroendocrine-like Transition in Patient-Derived...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Established prostate cancer cell lines poorly model the evolution to drug-resistant neuroendocrine disease.
• Patient-derived 3D ex vivo models offer a more accurate platform for studying prostate cancer progression and treatment resistance.

Purpose of the Study:

• To investigate the transition of early-stage prostate cancer to treatment-emergent neuroendocrine prostate cancer (t-NEPC) using patient-derived 3D ex vivo models.
• To identify molecular mechanisms and potential therapeutic vulnerabilities driving this transition.

Main Methods:

• Generated 3D tumor spheroid cultures from MRI-guided biopsies of early-stage prostate cancer patients.
• Selected spheroids with enzalutamide for 12 weeks to induce resistance and observed phenotypic changes.
• Utilized gene silencing (WSB1), drug inhibition (aliseptib, EZH2 inhibitors), and biochemical assays to elucidate molecular mechanisms.

Main Results:

• One patient-derived culture developed t-NEPC features, characterized by increased neuroendocrine markers (CgA, SYP) and decreased AR, PSA, and PSMA.
• WD repeat and SOCS box-containing protein 1 (WSB1) expression increased, correlating with PSMA degradation.
• WSB1 acts as an E3 ubiquitin ligase adaptor, promoting PSMA ubiquitination and degradation, a process influenced by AURKA.
• Targeting WSB1 or AURKA, alone or in combination with EZH2 inhibition, reduced resistant spheroid growth and increased apoptosis.

Conclusions:

• The AURKA-WSB1-PSMA signaling axis represents a critical vulnerability in enzalutamide-resistant and neuroendocrine-like prostate cancer.
• WSB1-mediated PSMA degradation is a key mechanism in the development of refractory prostate cancer.
• Inhibition of the AURKA-WSB1-PSMA axis shows therapeutic potential for advanced prostate cancer.