Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through
Won Kyung Kim1, Alyssa J Buckley1, Dong-Hoon Lee1
1Department of Cancer Biology and Molecular Medicine, Cancer Center and Beckman Research Institute, City of Hope, Duarte, CA, USA.
Abstract:
Androgen deprivation therapy (ADT) targeting androgen/androgen receptor (AR)- signaling pathways is the main therapy for advanced prostate cancer (PCa). However, ADT eventually fails in most patients who consequently develop castration-resistant prostate cancer (CRPC). While more potent AR antagonists and blockers for androgen synthesis were developed to improve clinical outcomes, they also show to induce more diverse CRPC phenotypes. Specifically, the AR- and neuroendocrine-null PCa, DNPC, occurs in abiraterone and enzalutamide-treated patients. Here, we uncover that current ADT induces aberrant HGF/MET signaling activation that further elevates Wnt/β-catenin signaling in human DNPC samples. Co-activation of HGF/MET and Wnt/β-catenin axes in mouse prostates induces DNPC-like lesions. Single-cell RNA sequencing analyses identify increased expression and activity of XPO1 and ribosomal proteins in mouse DNPC-like cells. Elevated expression of XPO1 and ribosomal proteins is also identified in clinical DNPC specimens. Inhibition of XPO1 and ribosomal pathways represses DNPC growth in both in vivo and ex vivo conditions, evidencing future therapeutic targets.
Insights
Androgen deprivation therapy for prostate cancer (PCa) can lead to castration-resistant PCa (CRPC). New research reveals aberrant HGF/MET and Wnt/β-catenin signaling drives a therapy-resistant PCa subtype, suggesting XPO1 and ribosomal pathways as future therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Androgen deprivation therapy (ADT) is standard for advanced prostate cancer (PCa).
- ADT resistance leads to castration-resistant prostate cancer (CRPC), with diverse phenotypes emerging.
- A specific subtype, androgen receptor (AR)- and neuroendocrine-null PCa (DNPC), arises after treatment with abiraterone and enzalutamide.
Purpose of the Study:
- To investigate the molecular mechanisms driving the development of DNPC.
- To identify novel therapeutic targets for DNPC.
Main Methods:
- Analysis of human DNPC samples and mouse models.
- Investigated aberrant signaling pathways including HGF/MET and Wnt/β-catenin.
- Utilized single-cell RNA sequencing to identify key molecular players.
- Assessed therapeutic potential of inhibiting XPO1 and ribosomal pathways.
Main Results:
- ADT induces aberrant HGF/MET signaling, which elevates Wnt/β-catenin signaling in human DNPC.
- Co-activation of HGF/MET and Wnt/β-catenin in mouse prostates induced DNPC-like lesions.
- Single-cell RNA sequencing revealed increased XPO1 and ribosomal protein expression in DNPC models and clinical samples.
- Inhibition of XPO1 and ribosomal pathways suppressed DNPC growth in vitro and in vivo.
Conclusions:
- Aberrant HGF/MET and Wnt/β-catenin signaling co-activation drives DNPC development.
- Elevated XPO1 and ribosomal protein pathways are critical for DNPC growth.
- Targeting XPO1 and ribosomal pathways represents a promising therapeutic strategy for DNPC.
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