Targeting the MLL complex in castration-resistant prostate cancer.
Malik R, Khan AP, Asangani IA, Cieslik M, Prensner JR, Wang X, Iyer MK, Jiang X, Borkin D, Escara-Wilke J, Stender R, Wu YM, Niknafs YS, Jing X, Qiao Y, Palanisamy N, Kunju LP, Krishnamurthy PM, Yocum AK, Mellacheruvu D, Nesvizhskii AI, Cao X, Dhanasekaran SM, Feng FY, Grembecka J, Cierpicki T, and Chinnaiyan AM. Targeting the MLL complex in castration-resistant prostate cancer. Nat Med 2015; 21(4):344-352.
Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has 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 protein (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 CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of 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 crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer.
Medical Subject Headings
Animals; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Drug Resistance, Neoplasm; Histone-Lysine N-Methyltransferase; Humans; Male; Mice; Mice, SCID; Myeloid-Lymphoid Leukemia Protein; Neoplasm Metastasis; Neoplasm Transplantation; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins; Receptors, Androgen; Signal Transduction; Treatment Outcome