Management of prostate cancer by targeting 3 beta HSD1 after enzalutamide and abiraterone treatment

Novel strategies for prostate cancer therapy are required to overcome resistance to abiraterone and enzalutamide. Here, we show that increasing 3 beta HSD1 after abiraterone and enzalutamide treatment is essential for drug resistance, and biochanin A (BCA), as an inhibitor of 3 beta HSD1, overcomes drug resistance. 3 beta HSD1 activity increases in cell lines, biopsy samples, and patients after long-term treatment with enzalutamide or abiraterone. Enhanced steroidogenesis, mediated by 3 beta HSD1, is sufficient to impair enzalutamide function. In patients, accelerated abiraterone metabolism results in a decline of plasma abiraterone as disease progresses. BCA inhibits 3 beta HSD1 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 3 beta HSD1 is a promising target to overcome drug resistance, and BCA suppresses disease progression as a 3 beta HSD1 inhibitor even after abiraterone and enzalutamide resistance.

Automated summary

Novel strategies are required to overcome drug resistance in prostate cancer. The study demonstrates that increasing 3 beta HSD1 is essential for drug resistance after abiraterone and enzalutamide treatment, and the inhibitor biochanin A (BCA) can overcome drug resistance. Furthermore, BCA also suppresses prostate cancer development.