Selective androgen receptor degrader (SARD) to overcome antiandrogen resistance in castration-resistant prostate cancer
- Chinese Academy of Medical Sciences & Peking Union Medical College, China
- Zhejiang Normal University, China
- Beijing Hospital, China
Abstract
In patients with castration-resistant prostate cancer (CRPC), clinical resistances such as androgen receptor (AR) mutation, AR overexpression, and AR splice variants (ARVs) limit the effectiveness of second-generation antiandrogens (SGAs). Several strategies have been implemented to develop novel antiandrogens to circumvent the occurring resistance. Here, we found and identified a bifunctional small molecule Z15, which is both an effective AR antagonist and a selective AR degrader. Z15 could directly interact with the ligand-binding domain (LBD) and activation function-1 region of AR, and promote AR degradation through the proteasome pathway. In vitro and in vivo studies showed that Z15 efficiently suppressed AR, AR mutants and ARVs transcription activity, downregulated mRNA and protein levels of AR downstream target genes, thereby overcoming AR LBD mutations, AR amplification, and ARVs-induced SGAs resistance in CRPC. In conclusion, our data illustrate the synergistic importance of AR antagonism and degradation in advanced prostate cancer treatment.
Data availability
Data Availability: All data generated or analysed during this study are included in the manuscript and supporting source files. The RNA sequence data could be found in the following link: https://bigd.big.ac.cn/gsa-human/browse/HRA000921. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD035721. PRIDE - Proteomics Identification Database (ebi.ac.uk).
Article and author information
Author details
Funding
National Natural Science Foundation of China (22077115,81672559,81311120299)
- Jinming Zhou
National Natural Science Foundation of China (82104231)
- Meng Wu
China Postdoctoral Science Foundation (2021M700504)
- Meng Wu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments have been approved by the Ethics Committee of Nanjing Lambda Pharmaceutical Co.,Ltd (Reference number: IACUC-20210902).
Copyright
© 2023, Wu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Selective androgen receptor degrader (SARD) to overcome antiandrogen resistance in castration-resistant prostate cancer
eLife 12:e70700.
https://doi.org/10.7554/eLife.70700
Further reading
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- Cell Biology
- Medicine
Background:
Pulmonary vascular remodeling is a progressive pathological process characterized by functional alterations within pulmonary artery smooth muscle cells (PASMCs) and adventitial fibroblasts (PAAFs). Mechanisms driving the transition to a diseased phenotype remain elusive.
Methods:
We combined transcriptomic and proteomic profiling with phenotypic characterization of source-matched cells from healthy controls and individuals with idiopathic pulmonary arterial hypertension (IPAH). Bidirectional cellular crosstalk was examined using direct and indirect co-culture models, and phenotypic responses were assessed via transcriptome analysis.
Results:
PASMC and PAAF undergo distinct phenotypic shifts during pulmonary vascular remodeling, with limited shared features, such as reduced mitochondrial content and hyperpolarization. IPAH-PASMC exhibit increased glycosaminoglycan production and downregulation of contractile machinery, while IPAH-PAAF display a hyperproliferative phenotype. We identified alterations in extracellular matrix components, including laminin and collagen, alongside pentraxin-3 and hepatocyte growth factor, as potential regulators of PASMC phenotypic transitions mediated by PAAF.
Conclusions:
While PASMCs and PAAFs retain their core cellular identities, they acquire distinct disease-associated states. These findings provide new insights into the dynamic interplay of pulmonary vascular mesenchymal cells in disease pathogenesis.
Funding:
This work was supported by Cardio-Pulmonary Institute EXC 2026 390649896 (GK) and Austrian Science Fund (FWF) grant I 4651-B (SC).
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- Cell Biology
- Medicine
In pulmonary hypertension, a combination of metabolic and mechanical dysfunction leads to irreversible vascular damage.
