Toward improving androgen receptor-targeted therapies in male-dominant hepatocellular carcinoma

AR is an oncogenic driver of hepatocellular carcinoma but AR-targeted therapy is limited by feedback activation of the AKT-mTOR pathway. Co-targeting of mTORC1 and AR might be an effective approach to HCC treatment. Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and a leading cause of cancer deaths worldwide. HCC is a male-dominant cancer with a male:female ratio of up to 7:1. The androgen receptor (AR) is the male hormone receptor known as a major oncogenic driver of prostate cancer. Although AR has been linked to the sexual dimorphism of HCC, clinical trials with AR-targeted agents failed to generate survival benefits. Recent studies provide new insights into the role of AR in liver tumorigenesis and therapeutic responses. Herein, we review current understanding of AR signaling in HCC and feedback mechanisms that limit response to AR blockade. New AR-targeting strategies that might improve outcomes in HCC therapies are also discussed.