2. Academic Validation
  3. Targeting the MLL complex in castration-resistant prostate cancer

Targeting the MLL complex in castration-resistant prostate cancer

  • Nat Med. 2015 Apr;21(4):344-52. doi: 10.1038/nm.3830.
Rohit Malik 1,  Amjad P Khan 1,  Irfan A Asangani 1,  Marcin Cieślik 1,  John R Prensner 1,  Xiaoju Wang 1,  Matthew K Iyer 1,  Xia Jiang 1,  Dmitry Borkin 2,  June Escara-Wilke 1,  Rachell Stender 1,  Yi-Mi Wu 1,  Yashar S Niknafs 3,  Xiaojun Jing 1,  Yuanyuan Qiao 1,  Nallasivam Palanisamy 4,  Lakshmi P Kunju 5,  Pranathi M Krishnamurthy 3,  Anastasia K Yocum 3,  Dattatreya Mellacheruvu 6,  Alexey I Nesvizhskii 7,  Xuhong Cao 8,  Saravana M Dhanasekaran 1,  Felix Y Feng 9,  Jolanta Grembecka 2,  Tomasz Cierpicki 2,  Arul M Chinnaiyan 10
Affiliations

Affiliations

  • 1 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • 2 Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • 3 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • 4 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] Department of Urology, Henry Ford Health System, Detroit, Michigan, USA.
  • 5 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.
  • 6 1] Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
  • 7 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] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
  • 8 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, USA.
  • 9 1] Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA. [2] Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA. [3] Department of Urology, University of Michigan, Ann Arbor, Michigan, USA.
  • 10 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.
PMID: 25822367 DOI: 10.1038/nm.3830
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.

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