Journal: Nature biomedical engineering
This study systematically interrogated nearly all possible single–amino acid changes in the androgen receptor (AR) ligand‑binding domain that can arise from single‑nucleotide variants, using high‑throughput prime editing (2,765 variants, covering 99.95% of this space).
Key points:
- Functional landscape of AR LBD
- • Identified 755 previously unrecognized non‑functional AR variants.
- • These data help distinguish pathogenic loss‑of‑function variants (relevant to androgen insensitivity syndrome) from benign or uncertain variants.
- Drug resistance profiling
- • Mapped resistance to the AR signaling inhibitor enzalutamide, discovering 225 new variants that maintain AR function despite drug exposure.
- • Identified 40 variants conferring resistance to the AR degrader bavdegalutamide.
- • This defines mutation “escape routes” for both an inhibitor and a degrader, with implications for next‑generation AR‑targeted agents and rational combination strategies.
- Clinical implications
- • Functional classification of AR variants supports improved diagnosis and interpretation of germline variants in androgen insensitivity syndrome.
- • In prostate cancer, the mutation–function map enables more accurate prognosis prediction based on a tumor’s AR mutation profile.
- • These insights support precision oncology approaches, including tailoring AR‑directed therapy to the specific mutation spectrum present in an individual’s tumor.