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High-resolution functional mapping of androgen receptor variants
Hyeong-Cheol Oh1,2, Yoojin Chang1,3, Jihye Park1,3
1Department of Pharmacology, Yonsei University College of Medicine, Seoul, Republic of Korea.
Abstract:
The androgen receptor (AR) plays a central role in the progression and therapy resistance of prostate cancer, the most common cancer in men. While AR signalling inhibitors such as enzalutamide are key treatments, their efficacy is often compromised by drug-resistant AR variants. In addition, mutations leading to germline loss of AR function cause androgen insensitivity syndrome, yet most AR variants are of uncertain significance. Here we use advanced prime editing to generate and assess 2,765 AR variants, covering 99.95% of all possible single amino acid variants encoded by single nucleotide variants in the ligand-binding domain. This mapping identified 755 new non-functional AR variants and revealed 225 and 40 new variants resistant to enzalutamide and bavdegalutamide, an AR degrader, respectively. Our findings also enabled prognosis prediction for patients with prostate cancer based on AR mutation profiles. The broader implications of the study include improved androgen insensitivity syndrome diagnosis, better prostate cancer prognosis prediction and precision treatments for patients with prostate cancer.
Insights
Researchers mapped 2,765 androgen receptor (AR) variants using prime editing, identifying new non-functional and drug-resistant forms. This advances understanding of prostate cancer and androgen insensitivity syndrome.
Area of Science:
- Molecular biology
- Genetics
- Oncology
Background:
- The androgen receptor (AR) is crucial in prostate cancer progression and treatment resistance.
- Current therapies like enzalutamide face challenges from drug-resistant AR variants.
- Germline AR loss-of-function mutations cause androgen insensitivity syndrome, but many AR variants have unknown significance.
Purpose of the Study:
- To comprehensively map single amino acid variants in the AR ligand-binding domain.
- To identify novel non-functional and drug-resistant AR variants.
- To improve diagnosis of androgen insensitivity syndrome and prognosis prediction for prostate cancer patients.
Main Methods:
- Utilized advanced prime editing technology.
- Generated and assessed 2,765 distinct AR variants.
- Covered 99.95% of single nucleotide variants in the AR ligand-binding domain.
Main Results:
- Identified 755 previously unknown non-functional AR variants.
- Discovered 225 new enzalutamide-resistant AR variants.
- Found 40 new bavdegalutamide-resistant AR variants.
Conclusions:
- Established a comprehensive variant map for the AR ligand-binding domain.
- Enabled better prediction of prostate cancer patient prognosis based on AR mutation profiles.
- Offers potential for improved androgen insensitivity syndrome diagnosis and precision prostate cancer treatments.
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