Deep Modeling of Gain‐of‐Function Mutations on Androgen Receptor

Abstract The efficiency of Androgen Receptor (AR) pathway inhibitors for prostate cancer (PCa) is on decline due to resistance mechanisms including the occurrence of gain‐of‐function mutations on human androgen receptor (AR). Hence, understanding and predicting such mutations is crucial for developing effective PCa treatment strategies. Leveraging accu‐ mulated data on clinically relevant AR mutants with recent advances in deep modeling techniques, this study aims to unveil and quantify critical AR mutation‐drug relation‐ ships. By incorporating molecular descriptors for drugs and mutated genes sequences, this work represented these features as single vectors and demonstrates their effective‐ ness in modeling AR mutant responses to conventional antiandrogens. The developed approach achieves above 80% accuracy in predicting the gain‐of‐function behavior of AR mutants and therefore can potentially uncover unknown agonist/antagonist relationships among mutant‐drug pairs.