Abstract Determination of molecular features that mediate clinically aggressive phenotypes in prostate cancer (PrCa) remains a major biological and clinical challenge. Here, we developed a biologically informed deep learning model (P-NET) to stratify PrCa patients by treatment resistance state and evaluate molecular drivers of treatment resistance for therapeutic targeting through complete model interpretability. Using a molecular cohort of 1,238 prostate cancers, we demonstrated that P-NET can predict cancer state using molecular data that is superior to other modeling approaches. Moreover, the biological interpretability within P-NET revealed established and novel molecularly altered candidates, such as MDM4 and FGFR1 , that were implicated in predicting advanced disease and validated in vitro . Broadly, biologically informed fully interpretable neural networks enable preclinical discovery and clinical prediction in prostate cancer and may have general applicability across cancer types.

Biologically informed deep neural network for prostate cancer classification and discovery