Targeting the MLL complex in castration resistant prostate cancer

Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration resistant prostate cancer (CRPC). Although prior work focused on targeting AR directly, co-activators of AR signaling—which may represent new therapeutic targets—are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia (MLL) complex, a well-known driver of MLL-fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via the menin MLL subunit. Menin expression is higher in castration resistant prostate cancer compared to hormone naïve prostate cancer and benign prostate and high menin expression correlates with poor overall survival. Treatment with a small molecule inhibitor of the menin-MLL interaction blocks AR signaling and inhibits the growth of castration resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a critical co-activator of AR and a potential therapeutic target in advanced prostate cancer.