Targeting the MLL complex in castration-resistant prostate cancer.

Document Type

Article

Publication Date

4-1-2015

Publication Title

Nature medicine

Abstract

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

PubMed ID

25822367

Volume

21

Issue

4

First Page

344

Last Page

352

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