High-resolution functional mapping of androgen receptor variants.

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.