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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Sudden death after myocardial infarction (MI) is associated with electrophysiological heterogeneities and ionic current remodelling. Low ejection fraction (EF) is used in risk stratification, but its mechanistic links with pro-arrhythmic heterogeneities are unknown. We aim to provide mechanistic explanations of clinical phenotypes in acute and chronic MI, from ionic current remodelling to ECG and EF, using human electromechanical modelling and simulation to augment experimental and clinical investigations. A human ventricular electromechanical modelling and simulation framework is constructed and validated with rich experimental and clinical datasets, incorporating varying degrees of ionic current remodelling as reported in literature. In acute MI, T-wave inversion and Brugada phenocopy were explained by conduction abnormality and local action potential prolongation in the border zone. In chronic MI, upright tall T-waves highlight large repolarisation dispersion between the border and remote zones, which promoted ectopic propagation at fast pacing. Post-MI EF at resting heart rate was not sensitive to the extent of repolarisation heterogeneity and the risk of repolarisation abnormalities at fast pacing. T-wave and QT abnormalities are better indicators of repolarisation heterogeneities than EF in post-MI.
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Background:
Under which conditions antibiotic combination therapy decelerates rather than accelerates resistance evolution is not well understood. We examined the effect of combining antibiotics on within-patient resistance development across various bacterial pathogens and antibiotics.
Methods:
We searched CENTRAL, EMBASE, and PubMed for (quasi)-randomised controlled trials (RCTs) published from database inception to 24 November 2022. Trials comparing antibiotic treatments with different numbers of antibiotics were included. Patients were considered to have acquired resistance if, at the follow-up culture, a resistant bacterium (as defined by the study authors) was detected that had not been present in the baseline culture. We combined results using a random effects model and performed meta-regression and stratified analyses. The trials’ risk of bias was assessed with the Cochrane tool.
Results:
42 trials were eligible and 29, including 5054 patients, qualified for statistical analysis. In most trials, resistance development was not the primary outcome and studies lacked power. The combined odds ratio for the acquisition of resistance comparing the group with the higher number of antibiotics with the comparison group was 1.23 (95% CI 0.68–2.25), with substantial between-study heterogeneity (I2=77%). We identified tentative evidence for potential beneficial or detrimental effects of antibiotic combination therapy for specific pathogens or medical conditions.
Conclusions:
The evidence for combining a higher number of antibiotics compared to fewer from RCTs is scarce and overall compatible with both benefit or harm. Trials powered to detect differences in resistance development or well-designed observational studies are required to clarify the impact of combination therapy on resistance.
Funding:
Support from the Swiss National Science Foundation (grant 310030B_176401 (SB, BS, CW), grant 32FP30-174281 (ME), grant 324730_207957 (RDK)) and from the National Institute of Allergy and Infectious Diseases (NIAID, cooperative agreement AI069924 (ME)) is gratefully acknowledged.
