Abstract
Novel strategies for prostate cancer therapy are required to overcome resistance to abiraterone and enzalutamide. Here, we show that increasing 3βHSD1 after abiraterone and enzalutamide treatment is essential for drug resistance, and biochanin A (BCA), as an inhibitor of 3βHSD1, overcomes drug resistance. 3βHSD1 activity increases in cell lines, biopsy samples, and patients after long-term treatment with enzalutamide or abiraterone. Enhanced steroidogenesis, mediated by 3βHSD1, is sufficient to impair enzalutamide function. In patients, accelerated abiraterone metabolism results in a decline of plasma abiraterone as disease progresses. BCA inhibits 3βHSD1 and suppresses prostate cancer development alone or together with abiraterone and enzalutamide. Daidzein, a BCA analog of dietary origin, is associated with higher plasma abiraterone concentrations and prevented prostate-specific antigen (PSA) increases in abiraterone-resistant patients. Overall, our results show that 3βHSD1 is a promising target to overcome drug resistance, and BCA suppresses disease progression as a 3βHSD1 inhibitor even after abiraterone and enzalutamide resistance.