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Targeting the MLL complex in castration-resistant prostate cancer. | LitMetric

Targeting the MLL complex in castration-resistant prostate cancer.

Nat Med

1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. [3] Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA. [4] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA. [5] Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, USA. [6] Department of Urology, University of Michigan, Ann Arbor, Michigan, USA.

Published: April 2015

AI Article Synopsis

  • Resistance to androgen deprivation therapies in castration-resistant prostate cancer (CRPC) is driven by increased androgen receptor (AR) activity, prompting exploration of co-activators of AR signaling as new therapeutic targets.
  • The study reveals that the mixed-lineage leukemia (MLL) complex acts as a co-activator for AR signaling, with AR directly interacting with the menin-MLL subunit.
  • Higher levels of menin are found in CRPC compared to hormone-naive prostate cancer, correlating with poor survival outcomes, and blocking the menin-MLL interaction using a small-molecule inhibitor hinders AR signaling and tumor growth in mouse models.

Article 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.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390530PMC
http://dx.doi.org/10.1038/nm.3830DOI Listing

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