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Updated: Aug 5, 2026
Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Metabolic CRISPR screening identifies RPE as a key regulator of acquired enzalutamide resistance through FKBP5
Jintao Hu1,2,3, Cong Lai1,2, Yunfei Xiao1,2
1Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Abstract:
Enzalutamide is a cornerstone therapy for castration-resistant prostate cancer (CRPC), yet acquired resistance remains a major clinical challenge. Although metabolic enzymes are increasingly recognized as modulators of therapeutic response, their specific roles-particularly their non-enzymatic functions-in sustaining enzalutamide resistance remain incompletely understood. In this study, we performed an in vivo screen using a custom metabolic CRISPR library in enzalutamide-treated xenografts and identified the pentose phosphate pathway enzyme ribulose-5-phosphate 3-epimerase (RPE) as a critical driver of enzalutamide resistance. Silencing RPE markedly restored enzalutamide sensitivity, enhanced apoptosis in vitro, and significantly suppressed tumor growth in both cell line-derived and patient-derived xenograft models. Mechanistically, RPE promoted resistance independently of its canonical enzymatic activity. Instead, RPE physically interacted with FKBP5 and promoted its ubiquitin-proteasome-mediated degradation. Loss of FKBP5 subsequently hyperactivated AKT signaling, leading to increased p-BAD and BCL-xL levels and suppression of enzalutamide-induced cell death. Conversely, disrupting the RPE-FKBP5 interaction or silencing RPE in vivo using a PSMA-targeted lipid nanoparticle system effectively abrogated these resistance phenotypes. Together, these findings illustrate how CRPC cells hijack the non-enzymatic function of a metabolic enzyme to evade antiandrogen therapy, establishing the RPE-driven degradation of FKBP5 and consequent AKT hyperactivation as a targetable vulnerability for overcoming enzalutamide resistance.
Insights
Metabolic enzyme ribulose-5-phosphate 3-epimerase (RPE) drives enzalutamide resistance in prostate cancer by degrading FKBP5. Targeting RPE restores sensitivity and offers a new therapeutic strategy for castration-resistant prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Metabolism
Background:
- Enzalutamide is a key treatment for castration-resistant prostate cancer (CRPC).
- Acquired resistance to enzalutamide is a significant clinical hurdle.
- The non-enzymatic roles of metabolic enzymes in resistance are not well understood.
Purpose of the Study:
- To identify metabolic enzymes contributing to enzalutamide resistance.
- To elucidate the mechanisms by which these enzymes promote resistance.
- To explore therapeutic strategies targeting identified resistance pathways.
Main Methods:
- In vivo CRISPR screen of metabolic enzymes in enzalutamide-treated xenografts.
- CRISPR library screening to identify resistance drivers.
- In vitro apoptosis assays and in vivo xenograft studies (cell line and patient-derived).
- Investigation of RPE-FKBP5 interaction and downstream signaling pathways (AKT, BAD, BCL-xL).
- PSMA-targeted lipid nanoparticle system for in vivo RPE silencing.
Main Results:
- Ribulose-5-phosphate 3-epimerase (RPE) was identified as a critical driver of enzalutamide resistance.
- Silencing RPE restored enzalutamide sensitivity, enhanced apoptosis, and suppressed tumor growth.
- RPE promoted resistance via non-enzymatic interaction with FKBP5, leading to its degradation.
- Loss of FKBP5 resulted in AKT hyperactivation, increased p-BAD and BCL-xL, and suppressed apoptosis.
- Targeting the RPE-FKBP5 interaction or using RPE silencing abrogated resistance phenotypes.
Conclusions:
- CRPC cells exploit the non-enzymatic function of RPE to evade enzalutamide therapy.
- The RPE-FKBP5-AKT axis represents a targetable vulnerability for overcoming enzalutamide resistance.
- RPE-mediated FKBP5 degradation is a novel mechanism of resistance to antiandrogen therapy.
